CARDIAC NEXT-GENERATION SEQUENCING PANELS · for Duchenne muscular dystrophy disease (DMD) will only be performed if indicated. For Duchenne muscular dystrophy, the copy numbers of

CARDIAC NEXT-GENERATION SEQUENCING PANELS

Mail: One Gustave L. Levy Place, Box 1497 1 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 New York, NY 10029 F: 212-241-0139 www.sema4.com

http://www.sema4.com/

Mail: One Gustave L. Levy Place, Box 1497 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 New York, NY 10029

2 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

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Mail: One Gustave L. Levy Place, Box 1497 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25

New York, NY 10029

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TABLE OF CONTENTS

GENETIC TESTING FOR INHERITED CARDIOVASCULAR CONDITIONS 6

GENETICS AND INDICATIONS 6

TESTING METHODS, SENSITIVITY, AND LIMITATIONS 7

TURNAROUND TIME 9

SPECIMEN AND SHIPPING REQUIREMENTS 9

CUSTOMER SERVICES AND GENETIC COUNSELING 10

THE COMPREHENSIVE CARDIOMYOPATHY PANEL 11

DILATED CARDIOMYOPATHY (DCM) SUBPANEL 23

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (ARVC) SUBPANEL 28

HYPERTROPHIC CARDIOMYOPATHY (HCM) SUBPANEL 30

LEFT VENTRICULAR NON-COMPACTION CARDIOMYOPATHY (LVNC) SUBPANEL 33

THE COMPREHENSIVE ARRHYTHMIAS PANEL 35

BRUGADA SYNDROME (BRS) SUBPANEL 40

CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT) SUBPANEL 42

LONG / SHORT QT SYNDROME (LQTS / SQTS) SUBPANEL 44

AORTOPATHIES PANEL 46

CONGENITAL HEART DISEASE (CHD) PANEL 49

FAMILIAL HYPERCHOLESTEROLEMIA (FH) PANEL 52

PULMONARY HYPERTENSION (PAH) PANEL 54

METABOLIC CARDIOMYOPATHY PANEL 55

NOONAN SPECTRUM DISORDERS PANEL 57

HEREDITARY HEMORRHAGIC TELANGIECTASIA PANEL 59

REFERENCES 60

DISCLAIMER 69



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Genetic Testing for INHERITED CARDIOVASCULAR CONDITIONS

Many cardiovascular diseases have a genetic background and can be inherited from parents to their offspring. Controlling for risk factors such as smoking, hypertension, high cholesterol, and diabetes, researchers have established genetic etiology’s significant contribution in cardiovascular disease through twin studies and investigations of families with early onset cardiac complications. For example, a monozygotic twin has a marked increase in risk of early cardiovascular mortality when the first twin has died due to cardiac complications. This in turn supports genetic testing of families in order to identify changes in genes and pathways whose altered functions affect cardiovascular outcomes. Further, genetic testing can improve diagnostic accuracy and refine family management by identifying the molecular etiology of disease.

Next-generation sequencing (NGS) technology is ideal for diagnostic testing of families and index cases with cardiovascular complications due to the extreme locus heterogeneity and phenotypic overlap between the genes involved. Sema4 utilizes Agilent SureSelectQXT target enrichment library prep with Illumina NovaSeq sequencing to detect pathogenic variants in genes involved in cardiovascular disease. A comprehensive menu of heritable cardiovascular conditions was curated by experts and relevant genes were selected based on literature review, clinical actionability scores, and comparison with commercially available assays. The Cardiac Panel includes 241 genes with the following subpanels: Comprehensive Cardiomyopathy (190), Dilated Cardiomyopathy (DCM; 57), Hypertrophic Cardiomyopathy (HCM; 40), Left Ventricular Non-Compaction Cardiomyopathy (LVNC; 20), Comprehensive Arrhythmias (54), Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC; 8), Brugada Syndrome (BrS; 20), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT; 8), Long / Short QT Syndrome (19), Aortopathies (33), Congenital Heart Disease (CHD; 44), Familial Hypercholesterolemia (FH; 4), Pulmonary Hypertension (10), Metabolic Cardiomyopathy (24), Noonan Spectrum Disorders (19), and Hereditary Hemorrhagic Telangiectasia Panel (5).

Customizable testing of the cardiac panel is available along with targeted familial testing. Genetic testing can help clarify the underlying cause of a cardiac complication, provide information on the likelihood of related health issues, and establish risk to other family members and future generations.

Genetics

The disorders included in this panel may be inherited in an autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), or isolated cases (IC) manner. For genes displaying an AD mode of inheritance, an affected parent carrying the mutated gene has a 50% chance of passing the variant on to an offspring, regardless of gender. Some of these genes are not fully penetrant, meaning that an individual may have a mutated gene but not display any of the signs/symptoms of the disorder. Additionally, these disorders may have variable expressivity indicating that individuals carrying the same pathogenic variant may display differing features and/or differing severity. For diseases with AR inheritance, the risk for a couple who are both carriers to have a child affected with the disease is 25% for each pregnancy. The parents of an affected child are most often obligate carriers (heterozygotes) and each carry one mutant allele (unless a de novo mutation occurs). An X-linked inheritance means that the risk of a male offspring with the disorder will be 50% if the mother carries an XL mutation. Depending on the X-inactivation pattern of the gene, a mother and her daughters may rarely be affected. Although X-linked diseases are normally transmitted from mother to son, transmission of an X-linked mutation will occur from an affected father to each daughter, but will not occur from father to son. An IC mode of inheritance indicates no prior family history.

Indications

1. Clinical status: to confirm a clinical diagnosis in an affected patient, in an individual with unknown status (no screening/evaluation), or in unaffected relatives of an affected patient (all screening/evaluations(s) normal). The purpose of the test may be diagnostic, carrier testing, familial follow-up on a known family variant, or prenatal testing for known variant(s).

2. Treatment: to clarify the cause of an individual’s cardiovascular disease, provide information on the likelihood

of related health issues, and guide treatment.



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3. Family risk: to establish risk to other family members and future generations.

For patients with a suspected syndrome or disorder, please consider single gene sequencing or associated subpanels prior to ordering the comprehensive panel.

Testing Methods, Sensitivity, and Limitations

Next Generation Sequencing (NGS) (Analytical Detection Rate >95%)

Agilent SureSelectTM QXT technology is used with a custom capture library to target the exonic regions and intron/exon splice junctions of the relevant genes, as well as a number of UTR, intronic or promoter regions that contain previously reported mutations. Samples are pooled and sequenced on the Illumina NovaSeq platform in the Xp workflow, using 100 bp paired-end reads. The sequencing data are analyzed using a custom bioinformatics algorithm designed and validated in-house. In our validation, average coverage was greater than 200X per sample with >99.9% of regions covered at greater than 20X.

The coding exons and splice junctions of the known protein-coding RefSeq genes are assessed for the average depth of coverage (minimum of 20X) and data quality threshold values. Most exons not meeting a minimum of >20X read depth across the exon are further analyzed by Sanger sequencing. Please note that several genomic regions present difficulties in mapping or obtaining read depth >20X. These regions include, but are not limited to, UTRs, promoters, and deep intronic areas. In addition, a mutation(s) in a gene not included on the panel could be present in this patient. The following regions (hg19 coordinates) have been excluded due to lack of amenability to NGS or Sanger sequencing, high GC content, high homology, lack of known clinically significant variants, or overlap with repetitive regions: ATP7A chrX:77269723-77269729, ATP7A chrX:77278955-77279156, DMD chrX:31897426-31897627, DMD chrX:32668999-32669253, DMD chrX:32644476-32644680, DMD chrX:31627637-31627838, DMD chrX:32460213-32460334, DMD chrX:31219361-31219367, DMD chrX:31219126-31219287, DMD chrX:32644160-32644321, FKTN chr9:108368751-108368962, FLNC chr7:128498050-128498282, GATA6 chr18:19749269-19749275, GBA chr1:155207120-155207380, GBA chr1:155204774-155204902, GBA chr1:155208296-155208452, LAMP2 chrX:119604075-119604081, LEFTY2 chr1:226127049-226127311, MUT chr6:49404225-49404231, NDUFS7 chr19:1386640-1386646, PGM1 chr1:64124731-64124737, RASA2 chr3:141235158-141235284, SCN1B chr19:35521713-35521775, SDHA chr5:251441-251594, SDHA chr5:251441,251594, SDHA chr5:218459-218544, SGSH chr17:78193967- 78194168, TBX1 chr22:19748416-19748814, TRDN chr6:123851639-123851721, TRDN chr6:123576214- 123576281, TTN chr2:179518142-179518245, TTN chr2:179518336-179518439, TTN chr2:179518532- 179518635, TTN chr2:179518727-179518833, TTN chr2:179518923-179519029, TTN chr2:179519160-

179519272, TTN chr2:179519460-179519566, TTN chr2:179519627-179519733, TTN chr2:179522213- 179522319, TTN chr2:179522402-179522505, TTN chr2:179522596:179522699, TTN chr2:179522792- 179522895, TTN chr2:179522987-179523093, TTN chr2:179523183-179523289, TTN chr2:179523420- 179523532, TTN chr2:179523720-179523826, TTN chr2:179523887-179523993, TTN chr2:179526474- 179526580, TTN chr2:179526663-179526766, TTN chr2:179526857-179526960, TTN chr2:179527053- 179527156, TTN chr2:179527248-179527354, TTN chr2:179527444-179527550, TTN chr2:179527681-

179527793, TTN chr2:179527981-179528087, and TTN chr2:179528148-179528254. The exons contained within these regions will not be reflexed to Sanger sequencing if the mapping quality or coverage is poor due to high sequence homology. Any variants identified during testing in these regions are confirmed by a second method and reported.

This test will detect variants within the exons and the intron-exon boundaries of the target regions. Variants outside these regions may not be detected, including, but not limited to, UTRs, promoters, and deep intronic areas, or regions that fall into the exceptions mentioned above. This technology may not detect all small insertion/deletions and is not diagnostic for repeat expansions and structural genomic variation. In addition, a mutation(s) in a gene not included on the panel could be present in this patient.

Copy Number Variant Analysis (Analytical Detection Rate >90%)

Large duplications and deletions were called from the relative read depths on an exon-by-exon basis using a custom Exome Hidden Markov Model (XHMM) algorithm. This algorithm is designed to pick up deletions and



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duplications of two or more exons/probed regions in length. For deletions (2 exons/probed regions), the analytical

sensitivity and analytical specificity are >99%. For duplications (2 exons/probed regions), the analytical sensitivity is >80% and analytical specificity is >99%. All reported pathogenic or likely pathogenic deletions and/or duplications were confirmed by a custom aCGH platform, quantitative PCR, and/or MLPA, depending on CNV size and gene content.

Multiplex Ligation-Dependent Probe Amplification (MLPA) (Analytical Detection Rate >99%)

MLPA probe sets and reagents from MRC-Holland are used for copy number analysis of specific targets versus known control samples. False positive or negative results may occur due to rare sequence variants in target regions detected by MLPA probes. Analytical sensitivity and specificity of the MLPA method are both 99%. MLPA for Duchenne muscular dystrophy disease (DMD) will only be performed if indicated. For Duchenne muscular dystrophy, the copy numbers of all DMD exons are analyzed. Potentially pathogenic single exon deletions and duplications are confirmed by a second method. Analysis of DMD is performed in association with sequencing of the coding regions.

Exon Array (Confirmation method) (Accuracy >99%)

The customized oligonucleotide microarray (Oxford Gene Technology) is a highly-targeted exon-focused array capable of detecting medically relevant microdeletions and microduplications at a much higher resolution than traditional aCGH methods. Each array matrix has approximately one hundred and eighty thousand 60-mer oligonucleotide probes that cover the entire gene panel. This platform is designed based on human genome NCBI Build 37 (hg19) and the CGH probes are selected to target the exonic regions of 222 genes. This test does not include analysis of ALPK3, CALM2, EIF2AK4, GDF2, LZTR1, MAT2A, MEIS2, MFAP5, MIB1, PET100, PLEKHM2, PPP1CB, PRKG1, RASA2, SLMAP, and SOS2. For the majority of genes there are a minimum of 4 probes per exon. For very large exons, probes are distributed evenly along the exon with 1 probe every 125 bp. In the untargeted backbone regions, this array has one probe every 42kb. All genomic coordinates are reported using

human genome NCBI Build 37 (hg19). Copy number aberrations are identified using the Aberration Detection

Method-2 (ADM2) algorithm with a sensitivity threshold of 6.0 (Agilent Technologies). The log2 ratio threshold values to detect aberrations are < -0.25 for copy number losses and > 0.25 for copy number gains. Please note that any inconsistencies in the reported biological familial relationships could significantly change the interpretation of these results. For reported CNVs with uncertain clinical significance, continued surveillance of the medical literature for new information is recommended.

The sensitivity of this assay is estimated to be greater than 99% for microdeletions and microduplications in the exonic regions of 224 medically-relevant genes. Variant interpretation and classification is performed based on the American College of Medical Genetics standards and guidelines for the interpretation of sequence variants (Richards et al, 2015). Frequency in control populations is evaluated based on the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/), the Database of Genomic Variants (http://dgv.tcag.ca/dgv/app/home), and 1000 genomes (http://www.1000genomes.org/) databases. Any benign polymorphisms identified during this analysis will not be reported. Variant interpretations, based on current knowledge, may change over time as more information arises.

The following aberrations will NOT be reported and parental studies will NOT be performed:

• CNVs that are considered benign based on coverage in the Database of Genomic Variants (DGV; <http://dgv.tcag.ca/>) and/or our internal laboratory CNV database

• Gains or losses of <500 kb that do not include any known genes (<http://www.ncbi.nlm.nih.gov/refseq/>)

• Gains or losses with no known clinical significance (based on gene content and/or coverage in the DGV)

• Copy number variation of ALPK3, CALM2, EIF2AK4, GDF2, LZTR1, MAT2A, MEIS2, MFAP5, MIB1, PET100, PLEKHM2, PPP1CB, PRKG1, RASA2, SLMAP, and SOS2.

• Copy number gains and losses associated with genetic susceptibility, quantitative trait loci, pharmacogenetic alleles, and cancer predisposition

• Copy number gains and losses that are < 1.0 Mb in size and that appear to be mosaic by aCGH due to atypical

log2 ratios, unless the affected region is determined to be clinically significant based on gene content and/or coverage in the DGV


http://exac.broadinstitute.org/)

http://dgv.tcag.ca/dgv/app/home)

http://www.1000genomes.org/)

http://dgv.tcag.ca/

http://www.ncbi.nlm.nih.gov/refseq/


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The aCGH technology cannot detect balanced rearrangements, such as reciprocal translocations, Robertsonian translocations, inversions and balanced insertions, or imbalances that are below the resolution of this array. This technology will also not detect point mutations or small insertion/deletions below this array’s resolution that cause frameshifts, imprinting defects or other epigenetic mutations, and may not detect low level mosaicism. The failure to detect an alteration at any locus does not exclude the diagnosis of any of the disorders represented on the microarray.

The aCGH technology cannot detect balanced rearrangements, such as reciprocal translocations, Robertsonian translocations, inversions and balanced insertions, or imbalances that are below the resolution of this array. This technology will also not detect point mutations or small insertion/deletions below this array’s resolution that cause frameshifts, imprinting defects or other epigenetic mutations, and may not detect low level mosaicism. The failure to detect an alteration at any locus does not exclude the diagnosis of any of the disorders represented on the microarray.

Quantitative PCR (Confirmation method) (Accuracy >99%)

The relative quantification PCR is utilized on a Roche Universal Library Probe (UPL) system, which relates the PCR signal of the target region in one group to another. To test for genomic imbalances, both sample DNA and reference DNA is amplified with primer/probe sets that specific to the target region and a control region with known genomic copy number. Relative genomic copy numbers are calculated based on the standard ∆∆Ct formula.

Sanger Sequencing (Confirmation method) (Accuracy >99%)

Sanger sequencing, as indicated, is performed using BigDye Terminator chemistry with the ABI 3730 DNA analyzer with target specific amplicons. It also may be used to supplement specific guaranteed target regions that fail NGS sequencing due to poor quality or low depth of coverage (<20 reads) or as a confirmatory method for NGS positive results. False negative results may occur if rare variants interfere with amplification or annealing.

Variant Interpretation and Reporting

Variant interpretation and classification was performed based on the American College of Medical Genetics Standards and guidelines for the interpretation of sequence variants (PMID:25741868). Frequency in control populations were evaluated based on the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/) , and Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Potentially pathogenic variants may be confirmed by Sanger sequencing if indicated. Familial samples are only tested for certain variants by Sanger sequencing if indicated. Variants classified as likely benign in the proband were not confirmed by Sanger sequencing. We cannot rule out the possibility that variants classified as uncertain clinical significance may contribute to disease. Any benign polymorphisms identified during this analysis were not reported. Variant interpretations, based on current knowledge, may change over time as more information arises.

Turnaround Time

Results are reported to the referring physician within 10-14 business days (for prenatal samples) and 3-4 weeks (for postnatal samples) from the receipt of the specimen. Please note only targeted analysis is performed for prenatal cases, where the familial gene and mutation(s) are known.

Specimen and Shipping Requirements

Postnatal blood samples: 2 yellow-top (ACD-A or ACD-B) or 2 lavender-top (EDTA) tubes, 5-10 mL of blood from the patient are required. One blood tube from both parents is requested.

Newborn/child: 1 yellow-top (ACD-A or ACD-B) or 1 lavender-top (EDTA) tube, 2 mL of blood from the patient are required. Additionally, 1 yellow-top (ACD-A or ACD-B) or 1 lavender-top (EDTA) 5-10 mL tube of blood from


http://exac.broadinstitute.org/

http://gnomad.broadinstitute.org/


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both parents is requested.

Prenatal Specimens: 2 confluent T-25 flasks of cultured cells (originating from amniotic fluid or chorionic villi) or more than 4 mg of direct CVS tissue, or 15 mL of direct amniotic fluid (AF) as well as 1 lavender-top (EDTA) 5- 10mL tube of blood from the pregnant patient and her partner are required. Note: parental blood samples are requested for confirmation studies necessary in some cases; maternal blood is also used for maternal cell contamination studies. Please note, prenatal analysis will only be performed for known parental variants.

Extracted DNA samples: We request 20 µL DNA (50-250 ng/µL) or at minimum require 10 µL DNA (50-250 ng/µL). Causes for rejection include impurities in the test or reference DNA samples, including NaCl or KCl (>40 mM) and other salts, phenol, ethanol, heparin, EDTA (>1.5 mM), and Fe, contaminated DNA, and low concentration of DNA (<20 ng/µL).

Saliva samples: We can accept saliva specimens upon request. Saliva samples should be collected in Oragene DNA (OG-500) kits by DNA Genotek. Please contact our laboratory to obtain saliva kits.

Cheek swab: 1 cheek swab specimen collected from ORAGENE kit from the patient is required. 1 cheek swab specimen collected from ORAGENE kit from both parents is requested.

Tubes of blood, cultured cells, direct CVS, and direct AF should be kept and shipped refrigerated or at room temperature (PLEASE DO NOT FREEZE). Please note that additional samples may be required for exon array studies if ordered.

Customer Services and Genetic Counseling

Include the following with each sample: • Completed and signed test requisition form and informed consent • Billing information or payment (include copy of insurance card) • Contact information for referring physician • Testing to be performed • Indication for testing, patient’s family history, ethnic background and prior relevant test results

Send same day or overnight (check for morning delivery) to:

Sema4 1428 Madison Avenue, Atran Bldg, Room 2-25 New York, NY 10029

Contact: [email protected] Tel: 212-241-7518 Fax: 212-241-0139


mailto:[email protected]


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THE COMPREHENSIVE CARDIOMYOPATHY PANEL

Cardiomyopathies refer to diseases of the heart muscle, which can be inherited or acquired. As cardiomyopathy worsens and the heart weakens, signs and symptoms of heart failure usually occur. These signs and symptoms can include shortness of breath with physical exertion, fatigue, and swelling in the ankles, feet, legs, abdomen, and veins of the neck. Genetic testing of genes associated with inherited forms should be considered if the presence of cardiomyopathy observed in a patient cannot be explained by an acquired etiology. The Comprehensive Cardiomyopathy Panel contains the following 190 genes with six well-established subpanels: Arrythmias, Arrhythmogenic Right Ventricular Cardiomyopathy, Dilated Cardiomyopathy, Hypertrophic Cardiomyopathy, Metabolic Cardiomyopathy, and Left Ventricular Non-compaction Cardiomyopathy. Further details about these subpanels are provided on subsequent pages.

Gene MIM Disease Category OMIM Phenotype Inheritance

ABCC9

601439

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Brugada Syndrome

614050: AD Atrial fibrillation, familial, 12 608569: Cardiomyopathy, dilated, 1O 239850: AD Hypertrichotic osteochondrodysplasia

AD

ACADVL 609575 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

201475: AR VLCAD deficiency AR

ACTA2

102620

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

611788: AD Aortic aneurysm, familial thoracic 6 614042: Moyamoya disease 5 613834: AD Multisystemic smooth muscle dysfunction syndrome

AD

ACTC1

102540

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction

612794: AD Atrial septal defect 5 613424: AD Cardiomyopathy, dilated, 1R

612098: AD Cardiomyopathy, hypertrophic, 11 613424: AD Left ventricular noncompaction 4

AD

ACTN2

102573

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Hypertrophic

612158: AD Cardiomyopathy, dilated, 1AA, with or without LVNC 612158: AD Cardiomyopathy, hypertrophic, 23,

AD



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Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy with or without LVNC

AGK 610345 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

614691: AR Cataract 38, AR 212350: AR Sengers syndrome

AR

AGL

610860

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy; Metabolic Cardiomyopathies

232400: AR Glycogen storage disease IIIa 232400: AR Glycogen storage disease IIIb

AR

AKAP9

604001

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; Comprehensive Arrythmias; Dilated Cardiomyopathy

611820: AD ?Long QT syndrome-11

AD

ALG1 605907 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

608540: AR Congenital disorder of glycosylation, type Ik

AR

ALG12 607144 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

607143: AR Congenital disorder of glycosylation, type Ig

AR

ALMS1 606844 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease

203800: AR Alstrom syndrome AR

ALPK3 617608 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

618052: AR Cardiomyopathy, familial hypertrophic 27

AR

ANK2

106410

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Catecholaminergic Polymorphic Ventricular Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias; Dilated Cardiomyopathy

600919: AD Cardiac arrhythmia, ankyrin-B-related 600919: AD Long QT syndrome 4

AD

ANKRD1

609599

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy

None

None

ARSB 611542 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

253200: AR Mucopolysaccharidosis type VI (Maroteaux-Lamy)

AR

BAG3

603883


613881: AD Cardiomyopathy, dilated, 1HH 612954: AD Myopathy, myofibrillar, 6

AD

BRAF

164757

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease; Noonan Spectrum Disorders

211980: Adenocarcinoma of lung, somatic 115150: AD Cardiofaciocutaneous syndrome Colorectal cancer, somatic (3) 613707: AD LEOPARD syndrome 3 Melanoma, malignant, somatic (3) Nonsmall cell lung cancer, somatic (3) 613706: AD Noonan syndrome 7

AD

CACNA1C

114205

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; Comprehensive Arrythmias; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Brugada Syndrome

611875: Brugada syndrome 3 601005: AD Timothy syndrome

AD

CACNA2D1

114204

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; Comprehensive Arrythmias; Brugada Syndrome

None

None

CACNB2

600003


611876: Brugada syndrome 4

None

CALM1

114180

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Catecholaminergic Polymorphic Ventricular Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias

616247: AD Long QT syndrome 14 614916: AD Ventricular tachycardia, catecholaminergic polymorphic, 4

AD

CALM2

114182


616249: AD Long QT syndrome 15

AD

CALM3

114183


None

None

CASQ2

114251

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Catecholaminergic Polymorphic Ventricular Tachycardia; Comprehensive Arrythmias

611938: AR Ventricular tachycardia, catecholaminergic polymorphic, 2

AR



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CAV3

601253

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; Comprehensive Arrythmias; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy

192600: AD Cardiomyopathy, familial hypertrophic 123320: AD Creatine phosphokinase, elevated serum 611818: AD Long QT syndrome 9 614321: AD Myopathy, distal, Tateyama type 606072: AD Rippling muscle disease

AD

CAVIN4 617714 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

None None

CBL

165360


607785: AD, SM ?Juvenile myelomonocytic leukemia 613563: AD Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia

AD, SM

CBS

613381


236200: AR Homocystinuria, B6-responsive and nonresponsive types 236200: AR Thrombosis, hyperhomocysteinemic

AR

CHRM2 118493 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

None None

COL3A1 120180 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

130050: AD Ehlers-Danlos syndrome, vascular type AD


130000: AD Ehlers-Danlos syndrome, classic type, 1 AD



COX10

602125

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

256000: AR, Mitochondrial Leigh syndrome due to mitochondrial COX4 deficiency

220110: AR, Mitochondrial Mitochondrial complex IV deficiency

AR

COX15

603646


615119: AR Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 256000: AR, Mitochondrial Leigh syndrome due to cytochrome c oxidase deficiency

AR

CPT2

600650


600649: AR CPT II deficiency, infantile 608836: AR CPT II deficiency, lethal neonatal 255110: AR, AD CPT II deficiency, myopathic, stress- induced

614212: AR, AD {Encephalopathy, acute, infection- induced, 4, susceptibility to}

AD, AR

CRYAB

123590

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

615184: AD Cardiomyopathy, dilated, 1II 613763: AR, AD Cataract 16, multiple types 608810: AD Myopathy, myofibrillar, 2 613869: AR Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related

AD, AR

CSRP3

600824


607482: ?Cardiomyopathy, dilated, 1M 612124: AD Cardiomyopathy, hypertrophic, 12

AD

CTNNA3 607667 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias

615616: AD Arrhythmogenic right ventricular dysplasia, familial, 13

AD

DES

125660

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy

604765: Cardiomyopathy, dilated, 1I 601419: AR, AD Myopathy, myofibrillar, 1 181400: AD Scapuloperoneal syndrome, neurogenic, Kaeser type

AD, AR

DMD

300377


300376: XLR Becker muscular dystrophy 302045: XL Cardiomyopathy, dilated, 3B 310200: XLR Duchenne muscular dystrophy

XLR, XL

DOLK

610746

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Metabolic Cardiomyopathies

610768: AR Congenital disorder of glycosylation, type Im

AR

DSC2

125645

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Arrythmogenic Right Ventricular Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy

610476: AR, AD Arrhythmogenic right ventricular dysplasia 11 610476: AR, AD Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair

AD, AR

DSG2 125671 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Arrythmogenic Right Ventricular

610193: AD Arrhythmogenic right ventricular dysplasia 10

AD



New York, NY 10029

14 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy

612877: Cardiomyopathy, dilated, 1BB

DSP

125647

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Arrythmogenic Right Ventricular Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Left Ventricular Ncompaction

607450: AD Arrhythmogenic right ventricular dysplasia 8 605676: AR Cardiomyopathy, dilated, with woolly hair and keratoderma 615821: AD Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis 609638: AR Epidermolysis bullosa, lethal acantholytic

612908: AD Keratosis palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome

AD, AR

DTNA 601239 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Left Ventricular Ncompaction

604169: AD Left ventricular noncompaction 1, with or without congenital heart defects

AD

ELAC2

605367


615440: AR Combined oxidative phosphorylation deficiency 17 614731: {Prostate cancer, hereditary, 2, susceptibility to}

AR

EMD

300384

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy

310300: XLR Emery-Dreifuss muscular dystrophy 1, XL

XLR, XL

EYA4 603550 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

605362: AD ?Cardiomyopathy, dilated, 1J 601316: AD Deafness, AD 10

AD

FBN1

134797


102370: AD Acromicric dysplasia 129600: AD Ectopia lentis, familial 614185: AD Geleophysic dysplasia 2 604308: MASS syndrome 616914: AD Marfan lipodystrophy syndrome 154700: AD Marfan syndrome

184900: AD Stiff skin syndrome 608328: AD Weill-Marchesani syndrome 2, dominant

AD

FBN2

612570


121050: AD Contractural arachnodactyly, congenital 616118: AD Macular degeneration, early-onset

AD

FHL1

300163

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy

300696: XLR Emery-Dreifuss muscular dystrophy 6, XL 300696: XLR Myopathy, XL, with postural muscle atrophy 300717: XLD Reducing body myopathy, XL 1a, severe, infantile or early childhood onset 300718: XL Reducing body myopathy, XL 1b, with late childhood or adult onset 300695: XLD Scapuloperoneal myopathy, XLD 300280: XLR ?Uruguay faciocardiomusculoskeletal syndrome

XLD, XLR, XL

FKRP

606596

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

613153: AR Muscular dystrophy- dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 606612: AR Muscular dystrophy- dystroglycanopathy (congenital with or without mental retardation), type B, 5

607155: AR Muscular dystrophy- dystroglycanopathy (limb-girdle), type C, 5

AR

FKTN

607440


611615: AR Cardiomyopathy, dilated, 1X 253800: AR Muscular dystrophy- dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 613152: AR Muscular dystrophy- dystroglycanopathy (congenital without mental retardation), type B, 4 611588: AR Muscular dystrophy- dystroglycanopathy (limb-girdle), type C, 4

AR

FLNA 300017 Comprehensive Cardiovascular; Comprehensive 314400: XLR Cardiac valvular dysplasia, XL XLD, XLR, XL



New York, NY 10029

15 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


Cardiomyopathy; Aortopathies 300048: XLR Congenital short bowel syndrome 300321: XL ?FG syndrome 2 305620: XLR Frontometaphyseal dysplasia 1 300049: XLD Heterotopia, periventricular 300048: XLR Intestinal pseudoobstruction, neuronal 309350: XLD Melnick-Needles syndrome

311300: XLD Otopalatodigital syndrome, type I 304120: XLD Otopalatodigital syndrome, type II 300244: XLD Terminal osseous dysplasia

FLNC

102565


Cardiomyopathy, familial hypertrophic, 26 (3) 617047: AD Cardiomyopathy, familial restrictive 5 614065: AD Myopathy, distal, 4 609524: AD Myopathy, myofibrillar, 5

AD

GAA

606800


232300: AR Glycogen storage disease II

AR

GATA4

600576

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease

607941: AD Atrial septal defect 2 614430: AD Atrioventricular septal defect 4 615542: AD ?Testicular anomalies with or without congenital heart disease 187500: AD Tetralogy of Fallot 614429: AD Ventricular septal defect 1

AD

GATA6

601656


614475: AD Atrial septal defect 9 614474: AD Atrioventricular septal defect 5 600001: AD Pancreatic agenesis and congenital heart defects 217095: Persistent truncus arteriosus 187500: AD Tetralogy of Fallot

AD

GATAD1 614518 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

614672: AR ?Cardiomyopathy, dilated, 2B AR

GBA

606463


608013: AR Gaucher disease, perinatal lethal 230800: AR Gaucher disease, type I 230900: AR Gaucher disease, type II 231000: AR Gaucher disease, type III 231005: AR Gaucher disease, type IIIC 127750: AD {Lewy body dementia, susceptibility to} 168600: IC, MF {Parkinson disease, late-onset, susceptibility to}

AD, AR, IC, MF

GBE1 607839 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

232500: AR Glycogen storage disease IV 263570: AR Polyglucosan body disease, adult form

AR

GJA5 121013 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias

614049: AD Atrial fibrillation, familial, 11 108770: AD Atrial standstill, digenic (GJA5/SCN5A)

AD

GLA

300644


301500: XL Fabry disease 301500: XL Fabry disease, cardiac variant

XL

GLB1

611458


230500: AR GM1-gangliosidosis, type I 230600: AR GM1-gangliosidosis, type II 230650: AR GM1-gangliosidosis, type III 253010: AR Mucopolysaccharidosis type IVB (Morquio)

AR

GPD1L

611778

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Brugada Syndrome


None

GUSB 611499 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

253220: AR Mucopolysaccharidosis VII AR

HADHA

600890


609016: AR Fatty liver, acute, of pregnancy 609016: AR HELLP syndrome, maternal, of pregnancy 609016: AR LCHAD deficiency 609015: AR Trifunctional protein deficiency

AR

HCN4

605206

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Left Ventricular Ncompaction; Brugada Syndrome

613123: Brugada syndrome 8 163800: AD Sick sinus syndrome 2

AD

HEXB 606873 Comprehensive Cardiovascular; Comprehensive 268800: AR Sandhoff disease, infantile, juvenile, AR



New York, NY 10029

16 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Metabolic Cardiomyopathies and adult forms

HRAS

190020


109800: {Bladder cancer, somatic} 218040: AD, IC Congenital myopathy with excess of muscle spindles

218040: AD, IC Costello syndrome 162900: {Nevus sebaceous or woolly hair nevus, somatic} 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic

137550: {Spitz nevus or nevus spilus, somatic} 188470: {Thyroid carcinoma, follicular, somatic}

AD, IC

IDUA

252800


607014: AR Mucopolysaccharidosis Ih 607015: AR Mucopolysaccharidosis Ih/s 607016: AR Mucopolysaccharidosis Is

AR

ILK 602366 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

None None

JAG1

601920


118450: AD Alagille syndrome 1 617992: ?Deafness, congenital heart defects, and posterior embryotoxon 187500: AD Tetralogy of Fallot

AD

JPH2 605267 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy

613873: AD Cardiomyopathy, hypertrophic, 17 AD

JUP

173325


611528: AD Arrhythmogenic right ventricular dysplasia 12 601214: AR Naxos disease

AD, AR

KCNA5

176267

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Pulmonary Hypertension

612240: AD Atrial fibrillation, familial, 7

AD

KCND3

605411


616399: AD Brugada syndrome 9 607346: AD Spinocerebellar ataxia 19

AD

KCNE1

176261

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; Comprehensive Arrythmias

612347: AR Jervell and Lange-Nielsen syndrome 2 613695: AD Long QT syndrome 5

AD, AR

KCNE2

603796


611493: Atrial fibrillation, familial, 4 613693: AD Long QT syndrome 6

AD

KCNE3

604433



None

KCNE5

300328


None

None

KCNH2

152427


613688: AD Long QT syndrome 2 613688: AD {Long QT syndrome 2, acquired, susceptibility to} 609620: Short QT syndrome 1

AD

KCNJ2

600681


170390: AD Andersen syndrome 613980: AD Atrial fibrillation, familial, 9 609622: Short QT syndrome 3

AD

KCNJ5

600734


613677: AD Hyperaldosteronism, familial, type III 613485: AD Long QT syndrome 13

AD

KCNJ8

600935


None

None

KCNQ1

607542


607554: AD Atrial fibrillation, familial, 3 220400: AR Jervell and Lange-Nielsen syndrome 192500: AD Long QT syndrome 1 192500: AD {Long QT syndrome 1, acquired, susceptibility to} 609621: AD Short QT syndrome 2

AD, AR



New York, NY 10029

17 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


KRAS

190070


108010: Arteriovenous malformation of the brain, somatic 109800: Bladder cancer, somatic 114480: Breast cancer, somatic 615278: Cardiofaciocutaneous syndrome 2 137215: Gastric cancer, somatic 601626: AD Leukemia, acute myeloid 211980: Lung cancer, somatic 609942: AD Noonan syndrome 3 260350: Pancreatic carcinoma, somatic 614470: AD RAS-associated autoimmune leukoproliferative disorder

163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic

AD

LAMA4 600133 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

615235: AD Cardiomyopathy, dilated, 1JJ AD

LAMP2

309060

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathies

300257: XLD Danon disease

XLD

LDB3

605906

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction

601493: AD Cardiomyopathy, dilated, 1C, with or without LVNC

601493: AD Cardiomyopathy, hypertrophic, 24 601493: AD Left ventricular noncompaction 3 609452: AD Myopathy, myofibrillar, 4

AD

LMNA

150330

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Left Ventricular Ncompaction

115200: AD Cardiomyopathy, dilated, 1A 605588: AR Charcot-Marie-Tooth disease, type 2B1 181350: AD Emery-Dreifuss muscular dystrophy 2, AD 616516: AR Emery-Dreifuss muscular dystrophy 3, AR 610140: AD Heart-hand syndrome, Slovenian type 176670: AR, AD Hutchinson-Gilford progeria 151660: AD Lipodystrophy, familial partial, type 2 212112: AD Malouf syndrome 248370: AR Mandibuloacral dysplasia 613205: AD Muscular dystrophy, congenital 275210: AR Restrictive dermopathy, lethal

AD, AR

MAP2K1

176872


615279: Cardiofaciocutaneous syndrome 3

None

MAP2K2

601263



None

MED12

300188


309520: XLR Lujan-Fryns syndrome 300895: XLR Ohdo syndrome, XL 305450: XLR Opitz-Kaveggia syndrome

XLR, XL

MIB1 608677 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Left Ventricular Ncompaction

615092: AD Left ventricular noncompaction 7 AD

MLYCD 606761 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

248360: AR Malonyl-CoA decarboxylase deficiency AR

MTO1 614667 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

614702: AR Combined oxidative phosphorylation deficiency 10

AR

MUT 609058 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

251000: AR Methylmalonic aciduria, mut(0) type AR

MYBPC3

600958

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction

615396: AD Cardiomyopathy, dilated, 1MM 115197: AD Cardiomyopathy, hypertrophic, 4 615396: AD Left ventricular noncompaction 10

AD

MYH11 160745 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

132900: AD Aortic aneurysm, familial thoracic 4 AD

MYH6

160710

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy

614089: Atrial septal defect 3 613252: Cardiomyopathy, dilated, 1EE 613251: AD Cardiomyopathy, hypertrophic, 14

AD



New York, NY 10029

18 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance 614090: {Sick sinus syndrome 3}

MYH7

160760


613426: AD Cardiomyopathy, dilated, 1S 192600: AD Cardiomyopathy, hypertrophic, 1 160500: AD Laing distal myopathy 613426: AD Left ventricular noncompaction 5 608358: AD Myopathy, myosin storage, AD 255160: AR Myopathy, myosin storage, AR

181430: AD Scapuloperoneal syndrome, myopathic type

AD, AR

MYL2 160781 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy


MYL3 160790 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy

608751: AR, AD Cardiomyopathy, hypertrophic, 8 AD, AR

MYLK 600922 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies


MYLK2 606566 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy

192600: AD Cardiomyopathy, hypertrophic, 1, digenic

AD

MYOM1 603508 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy

None None

MYOZ2 605602 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy


MYPN

608517


615248: AD Cardiomyopathy, dilated, 1KK 615248: AD Cardiomyopathy, familial restrictive, 4

615248: AD Cardiomyopathy, hypertrophic, 22 617336: AR Nemaline myopathy 11, AR

AD, AR

NDUFA10 603835 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

256000: AR, Mitochondrial Leigh syndrome AR


256000: AR, Mitochondrial Leigh syndrome due to mitochondrial complex 1 deficiency

AR


256000: AR, Mitochondrial Leigh syndrome due to mitochondrial complex I deficiency

AR



AR

NDUFAF2 609653 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

252010: AR, XLD, Mitochondrial Mitochondrial complex I deficiency

AR, XLD

NDUFAF6 612392 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy


AR

NDUFS3

603846



252010: AR, XLD, Mitochondrial Mitochondrial complex I deficiency

AR, XLD

NDUFS4

602694


256000: AR, Mitochondrial Leigh syndrome 252010: AR, XLD, Mitochondrial Mitochondrial complex I deficiency

AR, XLD

NDUFS7 601825 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

256000: AR, Mitochondrial Leigh syndrome AR

NDUFS8 602141 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy


AR

NEBL 605491 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

None None

NEXN

613121


613122: AD Cardiomyopathy, dilated, 1CC 613876: AD Cardiomyopathy, hypertrophic, 20

AD

NKX2-5

600584

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Congenital Heart Disease

108900: AD Atrial septal defect 7, with or without AV conduction defects 217095: Conotruncal heart malformations, variable 614435: AD Hypoplastic left heart syndrome 2 225250: AD Hypothyroidism, congenital nongoitrous, 5 187500: AD Tetralogy of Fallot 614432: AD Ventricular septal defect 3

AD

NOTCH1

190198

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies; Congenital Heart Disease

616028: AD Adams-Oliver syndrome 5 109730: AD Aortic valve disease 1

AD



New York, NY 10029

19 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


NPPA 108780 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias

612201: AD Atrial fibrillation, familial, 6 615745: AR Atrial standstill 2

AD, AR

NRAS

164790


114500: Colorectal cancer, somatic 162900: Epidermal nevus, somatic 137550: Melanocytic nevus syndrome, congenital, somatic 249400: Neurocutaneous melanosis, somatic 613224: AD Noonan syndrome 6 614470: ?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 188470: Thyroid carcinoma, follicular, somatic

AD

OBSCN Comprehensive Cardiovascular; Comprehensive

Cardiomyopathy; Dilated Cardiomyopathy

PCCA 232000 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

606054: AR Propionicacidemia AR

PCCB 232050 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathies

606054: AR Propionicacidemia AR

PDLIM3 605889 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy

None None

PET100 614770 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy


AR

PGM1 171900 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

614921: AR Congenital disorder of glycosylation, type It

AR

PHYH 602026 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

266500: AR Refsum disease AR

PKP2

602861

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Arrythmogenic Right Ventricular Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Brugada Syndrome


AD

PLEKHM2 609613 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Left Ventricular Ncompaction

None None

PLN

172405


609909: Cardiomyopathy, dilated, 1P 613874: AD Cardiomyopathy, hypertrophic, 18

AD

PLOD1 153454 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

225400: AR Ehlers-Danlos syndrome, kyphoscoliotic type, 1

AR

PMM2 601785 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

212065: AR Congenital disorder of glycosylation, type Ia

AR

PRDM16

605557

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Left Ventricular Ncompaction

615373: AD Cardiomyopathy, dilated, 1LL 615373: AD Left ventricular noncompaction 8

AD

PRKAG2

602743

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Hypertrophic Cardiomyopathy

600858: AD Cardiomyopathy, hypertrophic 6 261740: AD Glycogen storage disease of heart, lethal congenital 194200: ?AD Wolff-Parkinson-White syndrome

AD

PRKG1 176894 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies


PTPN11

176876

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease; Hypertrophic Cardiomyopathy; Noonan Spectrum Disorders

151100: AD LEOPARD syndrome 1 607785: Leukemia, juvenile myelomonocytic, somatic 156250: AD Metachondromatosis 163950: AD Noonan syndrome 1

AD

RAF1

164760

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Noonan Spectrum Disorders

615916: AD Cardiomyopathy, dilated, 1NN 611554: LEOPARD syndrome 2 611553: AD Noonan syndrome 5

AD

RANGRF

607954


None

None

RASA1 139150 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hereditary Hemorrhagic

605462: Basal cell carcinoma, somatic 608354: AD Capillary malformation-arteriovenous

AD



New York, NY 10029

20 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


Telangiectasia malformation 608355: AD Parkes Weber syndrome

RBM20 613171 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

613172: AD Cardiomyopathy, dilated, 1DD AD

RIT1

609591


615355: AD Noonan syndrome 8

AD

RYR2

180902

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Catecholaminergic Polymorphic Ventricular Tachycardia; Arrythmogenic Right Ventricular Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Left Ventricular Ncompaction

600996: AD Arrhythmogenic right ventricular dysplasia 2 604772: AD Ventricular tachycardia, catecholaminergic polymorphic, 1

AD

SCN10A

604427


615551: AD Episodic pain syndrome, familial, 2

AD

SCN1B

600235


615377: AD Atrial fibrillation, familial, 13 612838: Brugada syndrome 5 612838: Cardiac conduction defect, nonspecific 604233: AD Epilepsy, generalized, with febrile seizures plus, type 1 617350: AR Epileptic encephalopathy, early infantile, 52

AD, AR

SCN2B

601327



AD

SCN3B

608214


613120: AD Atrial fibrillation, familial, 16 613120: AD Brugada syndrome 7

AD

SCN4B

608256


611819: AD Atrial fibrillation, familial, 17 611819: AD Long QT syndrome-10

AD

SCN5A

600163

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; Comprehensive Arrythmias; Dilated Cardiomyopathy; Left Ventricular Ncompaction; Brugada Syndrome

614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E 113900: AD Heart block, nonprogressive 113900: AD Heart block, progressive, type IA 603830: AD Long QT syndrome-3

608567: AR Sick sinus syndrome 1 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1

AD, AR

SCO1 603644 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy


AR

SDHA

600857


613642: Cardiomyopathy, dilated, 1GG 256000: AR, Mitochondrial Leigh syndrome 252011: AR Mitochondrial respiratory chain complex II deficiency 614165: AD Paragangliomas 5

AD, AR

SDHAF1 612848 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

252011: AR Mitochondrial complex II deficiency AR

SGCD 601411 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

606685: Cardiomyopathy, dilated, 1L 601287: AR Muscular dystrophy, limb-girdle, AR 6

AR

SGSH 605270 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

252900: AR Mucopolysaccharidosis type IIIA (Sanfilippo A)

AR

SHOC2

602775


607721: AD Noonan-like syndrome with loose anagen hair

AD

SKI 164780 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

182212: AD Shprintzen-Goldberg syndrome AD

SLC22A5

603377

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Metabolic Cardiomyopathies

212140: AR Carnitine deficiency, systemic primary

AR

SLC25A20 613698 Comprehensive Cardiovascular; Comprehensive 212138: AR Carnitine-acylcarnitine translocase AR



New York, NY 10029

21 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Metabolic Cardiomyopathies deficiency

SLC2A10 606145 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

208050: AR Arterial tortuosity syndrome AR

SLMAP

602701


None

None

SMAD3 603109 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

613795: AD Loeys-Dietz syndrome 3 AD

SMAD4

600993

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies; Hereditary Hemorrhagic Telangiectasia

175050: AD Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 139210: AD Myhre syndrome

260350: Pancreatic cancer, somatic 174900: AD Polyposis, juvenile intestinal

AD

SNTA1

601017



AD

SOS1

182530


135300: AD ?Fibromatosis, gingival, 1 610733: AD Noonan syndrome 4

AD

SURF1

185620


616684: AR Charcot-Marie-Tooth disease, type 4K 256000: AR, Mitochondrial Leigh syndrome, due to COX IV deficiency

AR

TAZ

300394

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathies

302060: XLR Barth syndrome

XLR

TBX1

602054


217095: Conotruncal anomaly face syndrome 188400: AD DiGeorge syndrome

187500: AD Tetralogy of Fallot 192430: AD Velocardiofacial syndrome

AD

TBX5 601620 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease

142900: AD Holt-Oram syndrome AD

TCAP

604488


607487: AD Cardiomyopathy, hypertrophic, 25 601954: AR Muscular dystrophy, limb-girdle, AR 7

AD, AR

TGFB2 190220 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies


TGFB3

190230

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Arrythmogenic Right Ventricular Cardiomyopathy; Aortopathies; Comprehensive Arrythmias

107970: AD Arrhythmogenic right ventricular dysplasia 1 615582: AD Loeys-Dietz syndrome 5

AD

TGFBR1

190181


609192: AD Loeys-Dietz syndrome 1 132800: AD {Multiple self-healing squamous epithelioma, susceptibility to}

AD

TGFBR2

190182


614331: Colorectal cancer, hereditary nonpolyposis, type 6

133239: Esophageal cancer, somatic 610168: AD Loeys-Dietz syndrome 2

AD

TMEM43

612048


604400: AD Arrhythmogenic right ventricular dysplasia 5 614302: AD Emery-Dreifuss muscular dystrophy 7, AD

AD

TMEM70 612418 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

614052: AR Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2

AR

TMPO 188380 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy

None None

TNNC1

191040


611879: Cardiomyopathy, dilated, 1Z 613243: AD Cardiomyopathy, hypertrophic, 13

AD

TNNI3

191044


613286: Cardiomyopathy, dilated, 1FF 611880: AR ?Cardiomyopathy, dilated, 2A 115210: AD Cardiomyopathy, familial restrictive, 1 613690: AD Cardiomyopathy, hypertrophic, 7

AD, AR

TNNT2 191045 Comprehensive Cardiovascular; Comprehensive 601494: AD Cardiomyopathy, dilated, 1D AD



New York, NY 10029

22 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


Cardiomyopathy; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction

612422: AD Cardiomyopathy, familial restrictive, 3 115195: AD Cardiomyopathy, hypertrophic, 2 601494: AD Left ventricular noncompaction 6

TPM1

191010


611878: AD Cardiomyopathy, dilated, 1Y 115196: AD Cardiomyopathy, hypertrophic, 3

611878: AD Left ventricular noncompaction 9

AD

TRDN

603283


615441: AR Ventricular tachycardia, catecholaminergic polymorphic, 5, with or without muscle weakness

AR

TRPM4

606936


604559: AD Progressive familial heart block, type IB

AD

TTN

188840


604145: Cardiomyopathy, dilated, 1G 613765: AD Cardiomyopathy, familial hypertrophic, 9 608807: AR Muscular dystrophy, limb-girdle, AR 10 603689: Myopathy, proximal, with early respiratory muscle involvement

611705: AR Salih myopathy 600334: AD Tibial muscular dystrophy, tardive

AD, AR

TTR

176300


105210: AD Amyloidosis, hereditary, transthyretin- related 115430: AD Carpal tunnel syndrome, familial 145680: AD [Dystransthyretinemic hyperthyroxinemia]

AD

TXNRD2 606448 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

617825: AR ?Glucocorticoid deficiency 5 AR

VCL

193065


611407: Cardiomyopathy, dilated, 1W 613255: AD Cardiomyopathy, hypertrophic, 15

AD

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM; Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive).

2. DMD: The following DMD hg19 coordinates have been excluded from this assay: chrX:31897426-31897627, chrX:32668999-32669253,

chrX:32644476-32644680, chrX:31627637-31627838, chrX:32460213-32460334, chrX:31219361-31219367, chrX:31219126-31219287,

chrX:32644160-32644321

3. FKTN: The following FKTN hg19 coordinates have been excluded from this assay: chr9:108368751-108368962

4. FLNC: The following FLNC hg19 coordinates have been excluded from this assay: chr7:128498050-128498282

5. GATA6: The following GATA6 hg19 coordinates have been excluded from this assay: chr18:19749269-19749275

6. GBA: The following GBA hg19 coordinates have been excluded from this assay: chr1:155207120-155207380, chr1:155204774-

155204902, chr1:155208296-155208452

7. LAMP2: The following LAMP2 hg19 coordinates have been excluded from this assay: chrX:119604075-119604081

8. MUT: The following MUT hg19 coordinates have been excluded from this assay: chr6:49404225-49404231

9. NDUFS7: The following NDUFS7 hg19 coordinates have been excluded from this assay: chr19:1386640-1386646

10. PGM1: The following PGM1 hg19 coordinates have been excluded from this assay: chr1:64124731-64124737

11. SCN1B: The following SCN1B hg19 coordinates have been excluded from this assay: chr19:35521713-35521775

12. SDHA: The following SDHA hg19 coordinates have been excluded from this assay: chr5:251441-251594, chr5:254496-254632,

chr5:218459-218544

13. SGSH: The following SGSH hg19 coordinates have been excluded from this assay: chr17:78193967-78194168

14. TBX1: The following TBX1 hg19 coordinates have been excluded from this assay: chr22:19748416-19748814

15. TRDN: The following TRDN hg19 coordinates have been excluded from this assay: chr6:123851639-123851721, chr6:123576214- 123576281



New York, NY 10029

23 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com

DILATED CARDIOMYOPATHY (DCM) SUBPANEL

Dilated cardiomyopathy (DCM) is characterized by the presence of left ventricular dilation and left ventricular systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease. DCM usually presents with heart failure with symptoms of congestion, reduced cardiac output, arrhythmias, and/or thromboembolic disease. Right ventricular dilation may be present but is not necessary for the diagnosis. The most prevalent cause of DCMs is ischemic injury due to prior myocardial infarction from coronary artery disease.

The Dilated Cardiomyopathy (DCM) Subpanel contains the following 57 genes.


ABCC9

601439



AD

ACTC1

102540


612794: AD Atrial septal defect 5 613424: AD Cardiomyopathy, dilated, 1R 612098: AD Cardiomyopathy, hypertrophic, 11


AD

ACTN2

102573


612158: AD Cardiomyopathy, dilated, 1AA, with or without LVNC 612158: AD Cardiomyopathy, hypertrophic, 23, with or without LVNC

AD

AKAP9

604001



AD

ANK2

106410


600919: AD Cardiac arrhythmia, ankyrin-B- related 600919: AD Long QT syndrome 4

AD

ANKRD1

609599 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy

None

None

BAG3

603883



AD

CACNA1C

114205



AD

CAV3

601253


192600: AD Cardiomyopathy, familial hypertrophic 123320: AD Creatine phosphokinase, elevated serum 611818: AD Long QT syndrome 9

614321: AD Myopathy, distal, Tateyama type 606072: AD Rippling muscle disease

AD

CAVIN4

617714


None

None

CRYAB

123590


615184: AD Cardiomyopathy, dilated, 1II 613763: AR, AD Cataract 16, multiple types 608810: AD Myopathy, myofibrillar, 2 613869: AR Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related

AD, AR

CSRP3

600824



AD

DES

125660 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias; Dilated

604765: Cardiomyopathy, dilated, 1I 601419: AR, AD Myopathy, myofibrillar, 1 181400: AD Scapuloperoneal syndrome,

AD, AR



New York, NY 10029

24 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy; Hypertrophic Cardiomyopathy neurogenic, Kaeser type

DMD



XLR, XL

DOLK

610746

Comprehensive Cardiovascular;

Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Metabolic Cardiomyopathy


AR

DSC2

125645



AD, AR

DSG2

125671


610193: AD Arrhythmogenic right ventricular dysplasia 10 612877: Cardiomyopathy, dilated, 1BB

AD

DSP

125647


607450: AD Arrhythmogenic right ventricular dysplasia 8 605676: AR Cardiomyopathy, dilated, with woolly hair and keratoderma 615821: AD Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis 609638: AR Epidermolysis bullosa, lethal acantholytic 612908: AD Keratosis palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome

AD, AR

ELAC2

605367



614731: {Prostate cancer, hereditary, 2, susceptibility to}

AR

EMD

300384



XLR, XL

EYA4

603550 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

605362: AD ?Cardiomyopathy, dilated, 1J 601316: AD Deafness, AD 10

AD

FKTN

607440


611615: AR Cardiomyopathy, dilated, 1X 253800: AR Muscular dystrophy- dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 613152: AR Muscular dystrophy- dystroglycanopathy (congenital without mental retardation), type B, 4 611588: AR Muscular dystrophy- dystroglycanopathy (limb-girdle), type C, 4

AR

FLNC

102565



AD

GATAD1

614518


614672: AR ?Cardiomyopathy, dilated, 2B

AR

ILK


None

None

JUP

173325



AD, AR

LAMA4

600133


615235: AD Cardiomyopathy, dilated, 1JJ

AD

LAMP2 309060 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated

300257: XLD Danon disease XLD



New York, NY 10029

25 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy

LDB3

605906


601493: AD Cardiomyopathy, dilated, 1C, with or without LVNC 601493: AD Cardiomyopathy, hypertrophic, 24 601493: AD Left ventricular noncompaction 3 609452: AD Myopathy, myofibrillar, 4

AD

LMNA

150330



AD, AR

MYBPC3

600958


615396: AD Cardiomyopathy, dilated, 1MM 115197: AD Cardiomyopathy, hypertrophic, 4


AD

MYH6

160710


614089: Atrial septal defect 3 613252: Cardiomyopathy, dilated, 1EE 613251: AD Cardiomyopathy, hypertrophic, 14 614090: {Sick sinus syndrome 3}

AD

MYH7

160760


613426: AD Cardiomyopathy, dilated, 1S 192600: AD Cardiomyopathy, hypertrophic, 1 160500: AD Laing distal myopathy 613426: AD Left ventricular noncompaction 5 608358: AD Myopathy, myosin storage, AD 255160: AR Myopathy, myosin storage, AR 181430: AD Scapuloperoneal syndrome, myopathic type

AD, AR

MYPN

608517


615248: AD Cardiomyopathy, dilated, 1KK 615248: AD Cardiomyopathy, familial restrictive, 4 615248: AD Cardiomyopathy, hypertrophic, 22 617336: AR Nemaline myopathy 11, AR

AD, AR

NEBL


None

None

NEXN

613121



AD

OBSCN Comprehensive Cardiovascular;

Comprehensive Cardiomyopathy; Dilated Cardiomyopathy

PKP2

602861



AD

PLN

172405



AD

PRDM16

605557 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Left Ventricular Ncompaction


AD

RAF1 164760 Comprehensive Cardiovascular; 615916: AD Cardiomyopathy, dilated, 1NN AD



New York, NY 10029

26 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


Comprehensive Cardiomyopathy; Congenital Heart Disease; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Noonan Spectrum Disorders

611554: LEOPARD syndrome 2 611553: AD Noonan syndrome 5

RBM20

613171


613172: AD Cardiomyopathy, dilated, 1DD

AD

RYR2

180902



604772: AD Ventricular tachycardia, catecholaminergic polymorphic, 1

AD

SCN5A

600163


614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E 113900: AD Heart block, nonprogressive 113900: AD Heart block, progressive, type IA 603830: AD Long QT syndrome-3 608567: AR Sick sinus syndrome 1

272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1

AD, AR

SGCD

601411


606685: Cardiomyopathy, dilated, 1L 601287: AR Muscular dystrophy, limb-girdle, AR 6

AR

SLC22A5

603377 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Metabolic Cardiomyopathy


AR

TAZ

300394

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy


XLR

TCAP



AD, AR

TMEM43

612048



AD

TNNC1



AD

TNNI3

191044



AD, AR

TNNT2

191045


601494: AD Cardiomyopathy, dilated, 1D 612422: AD Cardiomyopathy, familial restrictive, 3 115195: AD Cardiomyopathy, hypertrophic, 2 601494: AD Left ventricular noncompaction 6

AD

TPM1

191010


611878: AD Cardiomyopathy, dilated, 1Y 115196: AD Cardiomyopathy, hypertrophic, 3 611878: AD Left ventricular noncompaction 9

AD

TTN

188840


604145: Cardiomyopathy, dilated, 1G 613765: AD Cardiomyopathy, familial hypertrophic, 9

608807: AR Muscular dystrophy, limb-girdle, AR 10 603689: Myopathy, proximal, with early respiratory muscle involvement 611705: AR Salih myopathy 600334: AD Tibial muscular dystrophy, tardive

AD, AR



New York, NY 10029

27 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


TTR

176300


105210: AD Amyloidosis, hereditary, transthyretin-related 115430: AD Carpal tunnel syndrome, familial 145680: AD [Dystransthyretinemic hyperthyroxinemia]

AD

TXNRD2


617825: AR ?Glucocorticoid deficiency 5

AR

VCL

193065



AD


2. DMD: The following DMD hg19 coordinates have been excluded from this assay: chrX:31897426-31897627, chrX:32668999-32669253,


chrX:32644160-32644321

3. FKTN: The following FKTN hg19 coordinates have been excluded from this assay: chr9:108368751-108368962





New York, NY 10029

28 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

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ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY (ARVC) SUBPANEL

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by right ventricular dysfunction, ventricular arrhythmias, and progressive fibrofatty replacement of the myocardium resulting in an increased risk of sudden death in young individuals and athletes. In particular, the arrhythmias in ARVC, which arise from the right ventricle, have left bundle branch block morphology, which can be seen with an electrocardiogram. Cardiac MRI studies have also identified regional left ventricular dysfunction among individuals with ARVC. Overall, ARVC is marked by age-dependent penetrance with most patients presenting in the second to fourth decade of life. Of note, males were more likely to have arrhythmia events in analyses of individuals with genetically confirmed ARVC. Since many forms of cardiomyopathy can mimic aspects of ARVC, clinical and genetic testing is recommended for proper management.

The Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Subpanel contains the following 8 genes.


DSC2

125645



AD, AR

DSG2

125671



AD

DSP

125647


607450: AD Arrhythmogenic right ventricular dysplasia 8 605676: AR Cardiomyopathy, dilated, with woolly hair and keratoderma 615821: AD Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis 609638: AR Epidermolysis bullosa, lethal acantholytic 612908: AD Keratosis palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome

AD, AR

JUP

173325



AD, AR

PKP2

602861



AD

RYR2

180902



AD

TGFB3

190230



AD

TMEM43

612048



AD



New York, NY 10029

29 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com




New York, NY 10029

30 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

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HYPERTROPHIC CARDIOMYOPATHY (HCM) SUBPANEL

Hypertrophic Cardiomyopathy (HCM) is a commonly inherited monogenic cardiac disease with variable expression and age-related penetrance. HCM is a condition in which the myocardium is enlarged (hypertrophied) without an obvious cause. This hypertrophy is generally asymmetric and can be associated with obstruction of ventricular outflow. The most prevalent mutations in HCM occur among genes encoding sarcomere proteins. The clinical manifestations are highly variable, ranging from asymptomatic left ventricular hypertrophy to arrhythmias with atrial fibrillation, which is the most common sustained arrhythmia in HCM.

The Hypertrophic Cardiomyopathy (HCM) Subpanel contains the following 40 genes.


ACTC1

102540


612794: AD Atrial septal defect 5 613424: AD Cardiomyopathy, dilated, 1R 612098: AD Cardiomyopathy, hypertrophic, 11 613424: AD Left ventricular noncompaction 4

AD

ACTN2

102573



AD

AGL

610860 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy; Metabolic Cardiomyopathy


AR

ANKRD1

609599


None

None

BAG3

603883



AD

CACNA1C

114205



AD

CAV3

601253


192600: AD Cardiomyopathy, familial hypertrophic 123320: AD Creatine phosphokinase, elevated serum 611818: AD Long QT syndrome 9 614321: AD Myopathy, distal, Tateyama type 606072: AD Rippling muscle disease

AD

CPT2

600650

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy; Metabolic Cardiomyopathy

600649: AR CPT II deficiency, infantile 608836: AR CPT II deficiency, lethal neonatal 255110: AR, AD CPT II deficiency, myopathic, stress-induced 614212: AR, AD {Encephalopathy, acute, infection-induced, 4, susceptibility to}

AD, AR

CSRP3

600824



AD

DES

125660



AD, AR

DMD



XLR, XL

FHL1

300163


300696: XLR Emery-Dreifuss muscular dystrophy 6, XL 300696: XLR Myopathy, XL, with postural muscle atrophy 300717: XLD Reducing body myopathy, XL 1a, severe, infantile or early childhood onset 300718: XL Reducing body myopathy, XL 1b, with late childhood or adult onset

XLD, XLR, XL



New York, NY 10029

31 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


300695: XLD Scapuloperoneal myopathy, XLD 300280: XLR ?Uruguay faciocardiomusculoskeletal syndrome

FLNC

102565



AD

GAA

606800



AR

GLA



XL

JPH2

605267


613873: AD Cardiomyopathy, hypertrophic, 17

AD

LAMP2

309060

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Left Ventricular Ncompaction; Metabolic Cardiomyopathy


XLD

LDB3

605906



AD

MYBPC3

600958


615396: AD Cardiomyopathy, dilated, 1MM 115197: AD Cardiomyopathy, hypertrophic, 4


AD

MYH6

160710


614089: Atrial septal defect 3

613252: Cardiomyopathy, dilated, 1EE 613251: AD Cardiomyopathy, hypertrophic, 14 614090: {Sick sinus syndrome 3}

AD

MYH7

160760



AD, AR

MYL2

160781



AD

MYL3

160790


Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy

608751: AR, AD Cardiomyopathy, hypertrophic, 8

AD, AR

MYLK2

606566 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy

192600: AD Cardiomyopathy, hypertrophic, 1, digenic

AD

MYOM1

603508


None

None

MYOZ2

605602 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic Cardiomyopathy


AD

MYPN

608517


615248: AD Cardiomyopathy, dilated, 1KK 615248: AD Cardiomyopathy, familial restrictive, 4 615248: AD Cardiomyopathy, hypertrophic, 22 617336: AR Nemaline myopathy 11, AR

AD, AR

NEXN

613121



AD

PDLIM3 605889 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hypertrophic

None None



New York, NY 10029

32 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Cardiomyopathy

PLN

172405



AD

PRKAG2

602743



AD

PTPN11

176876



AD

RAF1

164760



AD

TCAP



AD, AR

TNNC1

191040



AD

TNNI3

191044



AD, AR

TNNT2

191045



AD

TPM1

191010



AD

TTR

176300


105210: AD Amyloidosis, hereditary, transthyretin-related 115430: AD Carpal tunnel syndrome, familial 145680: AD [Dystransthyretinemic hyperthyroxinemia]

AD

VCL

193065



AD

1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM;

Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. DMD: The following DMD hg19 coordinates have been excluded from this assay: chrX:31897426-31897627, chrX:32668999-32669253,


chrX:32644160-32644321





New York, NY 10029

33 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

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LEFT VENTRICULAR NON-COMPACTION CARDIOMYOPATHY (LVNC) SUBPANEL

Left ventricular noncompaction cardiomyopathy (LVNC) is a congenital abnormality where the left ventricular myocardium fails to compact during embryonic development. The mechanism behind this disorder is thought to be an intrauterine arrest of myocardial development where pieces of muscle (trabeculations) fail to compact. The clinical presentation is variable and is associated with genetic heterogeneity. LVNC can range from asymptomatic to severe heart failure and sudden death. LVNC may occur in isolation or in association with congenital heart disease. LVNC also includes rhythm abnormalities including Wolff-Parkinson-White syndrome, conduction defects, and ventricular tachyarrhythmias. Higher occurrence of familial cases, facial dysmorphism, and congenital arrhythmias is observed in children.

The Left Ventricular Non-Compaction Cardiomyopathy (LVNC) Subpanel contains the following 20 genes.


ACTC1

102540



AD

DSP

125647


607450: AD Arrhythmogenic right ventricular dysplasia 8 605676: AR Cardiomyopathy, dilated, with woolly hair and keratoderma

615821: AD Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis 609638: AR Epidermolysis bullosa, lethal acantholytic 612908: AD Keratosis palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome

AD, AR

DTNA

601239 Comprehensive Cardiovascular;

Comprehensive Cardiomyopathy; Left Ventricular Ncompaction

604169: AD Left ventricular noncompaction 1, with or without congenital heart defects

AD

HCN4

605206



AD

LAMP2

309060



XLD

LDB3

605906



AD

LMNA

150330



AD, AR

MIB1 608677 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Left

615092: AD Left ventricular noncompaction 7 AD



New York, NY 10029

34 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Ventricular Ncompaction

MYBPC3

600958


615396: AD Cardiomyopathy, dilated, 1MM 115197: AD Cardiomyopathy, hypertrophic, 4 615396: AD Left ventricular noncompaction 10

AD

MYH7

160760



AD, AR

PLEKHM2

609613

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Left Ventricular Ncompaction

None

None

PLN

172405



AD

PRDM16

605557 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Left Ventricular Ncompaction


AD

RYR2

180902



AD

SCN5A

600163



601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E 113900: AD Heart block, nonprogressive 113900: AD Heart block, progressive, type IA 603830: AD Long QT syndrome-3 608567: AR Sick sinus syndrome 1 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1

AD, AR

TAZ

300394



XLR

TNNI3

191044



AD, AR

TNNT2

191045



AD

TPM1

191010



AD

VCL

193065



AD





New York, NY 10029

35 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

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THE COMPREHENSIVE ARRHYTHMIAS PANEL

Collectively, arrhythmias are disorders of cardiac ion channels and are commonly referred to as cardiac channelopathies. The maintenance of normal cardiac rhythm depends on the proper movement of ions mediating the action potential in each cardiac compartment. In arrhythmias, abnormalities in ion channel function manifest as electrocardiogram abnormalities and in most studies, individuals who are digenic/biallelic carriers have a more severe arrhythmia phenotype. Pathogenic variants in certain genes, which encode specific ion channels, have been shown to underlie well known heritable arrhythmogenic disorders occurring in the structurally normal heart. These include arrhythmogenic right ventricular cardiomyopathy, long and short QT syndromes, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). The Arrhythmias Panel contains the following 54 genes with four well-established subpanels: Arrythmogenic Right Ventricular Cardiomyopathy (ARVC), Brugada Syndrome (BrS), CPVT, and Long / Short QT Syndrome (LSQT).


ABCC9

601439



AD

ACTN2

102573



AD

AKAP9

604001

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; Comprehensive Arrythmias;


AD



New York, NY 10029

36 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com

Gene MIM Disease Category OMIM Phenotype Inheritance Dilated Cardiomyopathy

ANK2

106410



AD

CACNA1C

114205



AD

CACNA2D1

114204


None

None

CACNB2

600003



None

CALM1

114180



AD

CALM2

114182



AD

CALM3

114183


None

None

CASQ2

114251



AR

CAV3

601253


192600: AD Cardiomyopathy, familial hypertrophic 123320: AD Creatine phosphokinase, elevated serum

611818: AD Long QT syndrome 9 614321: AD Myopathy, distal, Tateyama type 606072: AD Rippling muscle disease

AD

CTNNA3

607667


Comprehensive Cardiomyopathy; Comprehensive Arrythmias

615616: AD Arrhythmogenic right ventricular dysplasia, familial, 13

AD

DES

125660



AD, AR

DSC2

125645



AD, AR

DSG2

125671



AD

DSP

125647

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Arrythmogenic Right Ventricular

Cardiomyopathy; Comprehensive Arrythmias; Dilated Cardiomyopathy; Left Ventricular

607450: AD Arrhythmogenic right ventricular dysplasia 8 605676: AR Cardiomyopathy, dilated, with woolly hair and keratoderma 615821: AD Dilated cardiomyopathy with woolly

AD, AR



New York, NY 10029

37 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


Ncompaction hair, keratoderma, and tooth agenesis 609638: AR Epidermolysis bullosa, lethal acantholytic 612908: AD Keratosis palmoplantaris striata II 607655: AR Skin fragility-woolly hair syndrome

EMD

300384



XLR, XL

GJA5

121013

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias

614049: AD Atrial fibrillation, familial, 11 108770: AD Atrial standstill, digenic (GJA5/SCN5A)

AD

GPD1L

611778



None

HCN4

605206



AD

JUP

173325



AD, AR

KCNA5

176267



AD

KCND3

605411



AD

KCNE1

176261



AD, AR

KCNE2

603796 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; Comprehensive Arrythmias


AD

KCNE3

604433



None

KCNE5

300328


None

None

KCNH2

152427



AD

KCNJ2

600681



AD

KCNJ5

600734



AD

KCNJ8

600935


None

None

KCNQ1

607542


607554: AD Atrial fibrillation, familial, 3 220400: AR Jervell and Lange-Nielsen syndrome

192500: AD Long QT syndrome 1 192500: AD {Long QT syndrome 1, acquired,

AD, AR



New York, NY 10029

38 CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139

www.sema4.com


susceptibility to} 609621: AD Short QT syndrome 2

LDB3

605906



AD

LMNA

150330


115200: AD Cardiomyopathy, dilated, 1A 605588: AR Charcot-Marie-Tooth disease, type 2B1 181350: AD Emery-Dreifuss muscular dystrophy 2, AD

616516: AR Emery-Dreifuss muscular dystrophy 3, AR 610140: AD Heart-hand syndrome, Slovenian type 176670: AR, AD Hutchinson-Gilford progeria 151660: AD Lipodystrophy, familial partial, type 2 212112: AD Malouf syndrome 248370: AR Mandibuloacral dysplasia 613205: AD Muscular dystrophy, congenital 275210: AR Restrictive dermopathy, lethal

AD, AR

NKX2-5

600584


108900: AD Atrial septal defect 7, with or without AV conduction defects 217095: Conotruncal heart malformations, variable 614435: AD Hypoplastic left heart syndrome 2 225250: AD Hypothyroidism, congenital nongoitrous, 5

187500: AD Tetralogy of Fallot 614432: AD Ventricular septal defect 3

AD

NPPA

108780 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Comprehensive Arrythmias

612201: AD Atrial fibrillation, familial, 6 615745: AR Atrial standstill 2

AD, AR

PKP2

602861



AD

PLN

172405



AD

PRKAG2

602743



AD

RANGRF

607954


None

None

RYR2

180902



AD

SCN10A

604427



AD

SCN1B

600235


615377: AD Atrial fibrillation, familial, 13 612838: Brugada syndrome 5

612838: Cardiac conduction defect, nonspecific 604233: AD Epilepsy, generalized, with febrile

AD, AR



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seizures plus, type 1 617350: AR Epileptic encephalopathy, early infantile, 52

SCN2B

601327



AD

SCN3B

608214



AD

SCN4B



AD

SCN5A

600163


614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E 113900: AD Heart block, nonprogressive 113900: AD Heart block, progressive, type IA 603830: AD Long QT syndrome-3 608567: AR Sick sinus syndrome 1 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1

AD, AR

SLMAP

602701


None

None

SNTA1

601017



AD

TGFB3

190230



AD

TMEM43

612048



AD

TRDN

603283



AR

TRPM4

606936



AD


Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive).





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BRUGADA SYNDROME (BrS) SUBPANEL

Brugada syndrome (BrS) is a channelopathy caused by genetic changes in transmembrane ion channels and cardiac conduction abnormalities that can result in sudden death. BrS is typically associated with a distinctive electrocardiogram (ECG) pattern in the absence of structural heart abnormalities. Of note, malignant arrhythmias and a previous history of syncopal episodes is a common presentation. Specifically, there is a ST-segment elevation in BrS within the right precordial ECG leads. The ST-segment elevation may be transient in nature and can be evoked by pharmacological sodium channel blockade. Other conduction defects can manifest as first- degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome. Loss-of- function mutations in the pore-forming subunit of the cardiac sodium channel have been causally related to the disease in a subset of cases. Although BrS is commonly considered a Mendelian disorder with autosomal dominant transmission, studies in families harboring BrS-related mutations have demonstrated low disease penetrance and, in some instances, absence of a familial mutation in some affected family members. An implantable cardioverter defibrillator is recommended for management of individuals with a history of syncope or cardiac arrest.

The Brugada Syndrome (BrS) Subpanel contains the following 20 genes.


ABCC9

601439



AD

CACNA1C

114205



AD

CACNA2D1

114204


None

None

CACNB2

600003



None

GPD1L

611778



None

HCN4

605206



AD

KCND3

605411



AD

KCNE3

604433



None

KCNE5

300328


None

None

KCNH2

152427



AD

KCNJ8

600935


None

None



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PKP2

602861



AD

RANGRF

607954


None

None

SCN10A

604427



AD

SCN1B

600235


615377: AD Atrial fibrillation, familial, 13 612838: Brugada syndrome 5 612838: Cardiac conduction defect, nonspecific 604233: AD Epilepsy, generalized, with febrile seizures plus, type 1 617350: AR Epileptic encephalopathy, early infantile, 52

AD, AR

SCN2B

601327



AD

SCN3B

608214



AD

SCN5A

600163


614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E 113900: AD Heart block, nonprogressive

113900: AD Heart block, progressive, type IA 603830: AD Long QT syndrome-3 608567: AR Sick sinus syndrome 1 272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1

AD, AR

SLMAP

602701


None

None

TRPM4

606936



AD





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treatment with β‐

‐

CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT) SUBPANEL

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited life threatening arrhythmia leading to syncope and sudden cardiac death at a young age. CPVT patients do not show any detectable cardiac disease

and in particular manifest ventricular premature beats and bidirectional or polymorphic ventricular tachycardia in response to emotional or physical stress. Spontaneous recovery may occur when these arrhythmias self-

terminate. However, in other instances, the ventricular tachycardia can degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation (CPR) is not performed. The common genetic form of CPVT is associated with autosomal dominant mutations in the cardiac ryanodine receptor, however there is also a very

rare form linked to recessive mutations in calsequestrin. Current clinical management of CPVT is based on blockers to reduce the frequency of arrhythmias and the implantation of automated defibrillators

to terminate fatal arrhythmias.

The Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Subpanel contains the following 8 genes.


ANK2

106410


600919: AD Cardiac arrhythmia, ankyrin-B- related


AD

CALM1

114180



AD

CALM2

114182



AD

CALM3

114183

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Catecholaminergic Polymorphic Ventricular

Tachycardia; Long / Short Qt Syndrome; Comprehensive Arrythmias

None

None

CASQ2

114251



AR

KCNJ2

600681



AD

RYR2

180902



AD

TRDN

603283



AR




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Treatment options typically involve β‐

LONG / SHORT QT SYNDROME (LQTS / SQTS) SUBPANEL

Inherited arrhythmias such as long QT syndrome (LQTS) or short QT syndrome (SQTS) occur in a heterogeneous collection of Mendelian disorders, often leading to sudden cardiac death. These disorders are usually caused by rare, highly penetrant mutations in ion channel genes. LQTS is characterized by a prolongation of the QT interval and T-wave abnormalities on electrocardiograms along with a propensity to ventricular tachyarrhythmias, which lead to syncope and/or cardiac arrest. The fundamental arrhythmogenic triggering mechanisms are linked to the decreased outward potassium currents in LQTS. In contrast, SQTS is characterized by a short QT interval with the late portion of the T-wave being statistically prolonged in most SQTS reports. Individuals with SQTS may manifest symptoms such as syncope, cardiac arrest, atrial fibrillation, idiopathic ventricular fibrillation, bradycardia and irregular rhythm. However, for both syndromes, an abnormal QT interval is not always associated with an increased risk of cardiac events since a wide range of QT intervals are considered abnormal without a significant increase in risk. Additional risk factors can include administration of certain medications such as antidepressants or cholesterol-lowering drugs that can exacerbate the QT interval profile.

blockers and implantable cardioverter-defibrillators as therapeutic options to

prevent cardiac arrest.

The Long / Short QT Syndrome Subpanel contains the following 19 genes.


AKAP9

604001



AD

ANK2

106410



AD

CACNA1C

114205



AD

CACNA2D1

114204


None

None

CACNB2

600003



None

CALM1

114180



AD

CALM2

114182



AD

CALM3

114183


None

None

CAV3

601253


192600: AD Cardiomyopathy, familial hypertrophic 123320: AD Creatine phosphokinase, elevated serum 611818: AD Long QT syndrome 9 614321: AD Myopathy, distal, Tateyama type

AD



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Gene MIM Disease Category OMIM Phenotype Inheritance 606072: AD Rippling muscle disease

KCNE1



AD, AR

KCNE2

603796


Comprehensive Cardiomyopathy; Long / Short Qt Syndrome; Comprehensive Arrythmias


AD

KCNH2

152427



613688: AD {Long QT syndrome 2, acquired, susceptibility to} 609620: Short QT syndrome 1

AD

KCNJ2

600681


170390: AD Andersen syndrome 613980: AD Atrial fibrillation, familial, 9

609622: Short QT syndrome 3

AD

KCNJ5



AD

KCNQ1

607542


607554: AD Atrial fibrillation, familial, 3 220400: AR Jervell and Lange-Nielsen syndrome

192500: AD Long QT syndrome 1 192500: AD {Long QT syndrome 1, acquired, susceptibility to} 609621: AD Short QT syndrome 2

AD, AR

SCN4B



AD

SCN5A

600163


614022: AD Atrial fibrillation, familial, 10 601144: AD Brugada syndrome 1 601154: AD Cardiomyopathy, dilated, 1E 113900: AD Heart block, nonprogressive 113900: AD Heart block, progressive, type IA 603830: AD Long QT syndrome-3 608567: AR Sick sinus syndrome 1

272120: AR {Sudden infant death syndrome, susceptibility to} 603829: Ventricular fibrillation, familial, 1

AD, AR

SNTA1



AD

TRDN

603283



AR


Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. TRDN: The following TRDN hg19 coordinates have been excluded from this assay: chr6:123851639-123851721, chr6:123576214-

123576281



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AORTOPATHIES PANEL

Aortopathies account for a significant healthcare burden that is likely underestimated and underdiagnosed due to early mortality caused by aneurysms. Typically, aortopathies are subcategorized into thoracic abdominal aortic aneurysm and abdominal aortic aneurysm. Abdominal aortic aneurysms are common degenerative disorders associated with traditional atherosclerotic risk factors such as advanced age, cigarette smoking, hypertension, and hypercholesterolemia. These aneurysms tend to arise from complicated interactions of multiple predisposing genes and environmental risk factors. By contrast, thoracic abdominal aneurysms occur across all age groups and can present as part of a genetic syndrome or an isolated anomaly. Most genetic causes of heritable aortopathies are transmitted as monogenic defects with autosomal dominant patterns of inheritance associated with high penetrance. Notably, since clinical variability between and within genetic subtypes is a hallmark of aortic disease, next-generation sequencing is a robust method to delineate loci associated with the hereditary aortopathies.

The Aortopathies Panel contains the following 33 genes.


ACTA2

102620


611788: AD Aortic aneurysm, familial thoracic 6 614042: Moyamoya disease 5 613834: AD Multisystemic smooth muscle dysfunction syndrome

AD

ADAMTS2 604539 Comprehensive Cardiovascular; Aortopathies 225410: AR Ehlers-Danlos syndrome, dermatosparaxis type

AR

ATP7A

300011

Comprehensive Cardiovascular; Aortopathies

309400: XLR Menkes disease 304150: XLR Occipital horn syndrome 300489: XLR Spinal muscular atrophy, distal, XL 3

XLR, XL

CBS

613381


236200: AR Homocystinuria, B6-responsive and nonresponsive types 236200: AR Thrombosis, hyperhomocysteinemic

AR

CHST14 608429 Comprehensive Cardiovascular; Aortopathies 601776: AR Ehlers-Danlos syndrome, musculocontractural type 1

AR

COL1A1

120150


166710: AD {Bone mineral density variation QTL, osteoporosis} 114000: AD Caffey disease 130060: AD Ehlers-Danlos syndrome, arthrochalasia type, 1 166200: AD Osteogenesis imperfecta, type I 166210: AD Osteogenesis imperfecta, type II 259420: AD Osteogenesis imperfecta, type III 166220: AD Osteogenesis imperfecta, type IV

AD

COL1A2

120160


617821: AD Ehlers-Danlos syndrome, arthrochalasia type, 2 225320: AR Ehlers-Danlos syndrome, cardiac valvular type 259420: AD imperfecta, type III 166210: AD Osteogenesis imperfecta, type II 166220: AD Osteogenesis imperfecta, type IV 166710: AD {Osteoporosis, postmenopausal}

AD, AR


130050: AD Ehlers-Danlos syndrome, vascular type

AD




130010: AD Ehlers-Danlos syndrome, classic type, 2

AD

EFEMP2 604633 Comprehensive Cardiovascular; Aortopathies 614437: AR Cutis laxa, AR, type IB AR

FBN1

134797


102370: AD Acromicric dysplasia 129600: AD Ectopia lentis, familial 614185: AD Geleophysic dysplasia 2 604308: MASS syndrome

AD



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616914: AD Marfan lipodystrophy syndrome 154700: AD Marfan syndrome 184900: AD Stiff skin syndrome 608328: AD Weill-Marchesani syndrome 2, dominant

FBN2

612570 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

121050: AD Contractural arachnodactyly, congenital 616118: AD Macular degeneration, early-onset

AD

FKBP14 614505 Comprehensive Cardiovascular; Aortopathies 614557: AR Ehlers-Danlos syndrome, kyphoscoliotic type, 2

AR

FLNA

300017


314400: XLR Cardiac valvular dysplasia, XL 300048: XLR Congenital short bowel syndrome 300321: XL ?FG syndrome 2 305620: XLR Frontometaphyseal dysplasia 1 300049: XLD Heterotopia, periventricular 300048: XLR Intestinal pseudoobstruction, neuronal 309350: XLD Melnick-Needles syndrome 311300: XLD Otopalatodigital syndrome, type I 304120: XLD Otopalatodigital syndrome, type II 300244: XLD Terminal osseous dysplasia

XLD, XLR, XL

MAT2A 601468 Comprehensive Cardiovascular; Aortopathies None None

MED12

300188


309520: XLR Lujan-Fryns syndrome 300895: XLR Ohdo syndrome, XL 305450: XLR Opitz-Kaveggia syndrome

XLR, XL

MFAP5 601103 Comprehensive Cardiovascular; Aortopathies 616166: AD Aortic aneurysm, familial thoracic 9 AD

MYH11 160745 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies 132900: AD Aortic aneurysm, familial thoracic 4 AD

MYLK 600922 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies


NOTCH1

190198 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies; Congenital Heart Disease


AD

PLOD1 153454 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

225400: AR Ehlers-Danlos syndrome, kyphoscoliotic type, 1

AR

PRKG1 176894 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies 615436: AD Aortic aneurysm, familial thoracic 8 AD

SKI 164780 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

182212: AD Shprintzen-Goldberg syndrome AD

SLC2A10 606145 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

208050: AR Arterial tortuosity syndrome AR

SLC39A13 608735 Comprehensive Cardiovascular; Aortopathies 612350: AR Ehlers-Danlos syndrome, spondylodysplastic type, 3

AR

SMAD3 603109 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies


SMAD4

600993

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies; Hereditary Hemorrhagic Telangiectasia

175050: AD Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 139210: AD Myhre syndrome 260350: Pancreatic cancer, somatic 174900: AD Polyposis, juvenile intestinal

AD

SMAD6

602931 Comprehensive Cardiovascular; Aortopathies; Congenital Heart Disease

614823: AD Aortic valve disease 2 617439: AD {Craniosynostosis 7, susceptibility to}

AD

TGFB2 190220 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies


TGFB3

190230



AD

TGFBR1

190181 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies

609192: AD Loeys-Dietz syndrome 1 132800: AD {Multiple self-healing squamous epithelioma, susceptibility to}

AD

TGFBR2

190182


614331: Colorectal cancer, hereditary nonpolyposis, type 6 133239: Esophageal cancer, somatic 610168: AD Loeys-Dietz syndrome 2

AD



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2. ATP7A: The following ATP7A hg19 coordinates have been excluded from this assay: chrX:77269723-77269729, chrX:77278955- 77279156



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CONGENITAL HEART DISEASE (CHD) PANEL

Congenital heart disease (CHD) is a common cause of neonatal morbidity and mortality. CHD can present in multifactorial and syndromic forms. CHD-associated genetic syndromes may occur in association with teratogens, chromosomal abnormalities, or single gene defects. A genetics evaluation is warranted in neonates who have congenital cardiac malformations associated with unusual physical features or other organ system malformations. Early molecular diagnosis of CHD-associated genetic syndromes is important as the genetic etiology may guide further diagnosis, management, and treatment. In addition, the presence of a syndrome in the family may warrant genetic counseling for the patient’s family.

The Congenital Heart Disease (CHD) Panel contains the following 43 genes.


ACTC1

102540



AD

ACVR2B 602730 Comprehensive Cardiovascular; Congenital Heart Disease

613751: Heterotaxy, visceral, 4, autosomal None

ALMS1 606844 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease

203800: AR Alstrom syndrome AR

BCOR 300485 Comprehensive Cardiovascular; Congenital Heart Disease

300166: XLD Microphthalmia, syndromic 2 XLD

BRAF

164757



AD

CBL

165360



AD, SM

CHD7

608892

Comprehensive Cardiovascular; Congenital Heart Disease

214800: AD CHARGE syndrome 612370: AD Hypogonadotropic hypogonadism 5 with or without anosmia

AD

CRELD1

607170


606217: AD Atrioventricular septal defect, partial, with heterotaxy syndrome

606217: AD {Atrioventricular septal defect, susceptibility to, 2}

AD

DNAH5 603335 Comprehensive Cardiovascular; Congenital Heart Disease

608644: Ciliary dyskinesia, primary, 3, with or without situs inversus

None

ELN 130160 Comprehensive Cardiovascular; Congenital Heart Disease

123700: AD Cutis laxa, AD 185500: AD Supravalvar aortic stenosis

AD

FOXH1 603621 Comprehensive Cardiovascular; Congenital Heart Disease

None None

GATA4

600576


607941: AD Atrial septal defect 2 614430: AD Atrioventricular septal defect 4 615542: AD ?Testicular anomalies with or without congenital heart disease

187500: AD Tetralogy of Fallot 614429: AD Ventricular septal defect 1

AD

GATA6

601656


614475: AD Atrial septal defect 9 614474: AD Atrioventricular septal defect 5 600001: AD Pancreatic agenesis and congenital

AD



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heart defects 217095: Persistent truncus arteriosus 187500: AD Tetralogy of Fallot

GDF1

602880


613854: AD Congenital heart defects, multiple types, 6 208530: AR Right atrial isomerism (Ivemark)

AD, AR

GJA1

121014


600309: AD Atrioventricular septal defect 3 218400: AR Craniometaphyseal dysplasia, AR 617525: AD Erythrokeratodermia variabilis et progressiva 3 241550: AR Hypoplastic left heart syndrome 1 164200: AD Oculodentodigital dysplasia 257850: AR Oculodentodigital dysplasia, AR 104100: AD Palmoplantar keratoderma with congenital alopecia 186100: AD Syndactyly, type III

AD, AR

GPC3

300037


312870: XLR Simpson-Golabi-Behmel syndrome, type 1 194070: Wilms tumor, somatic

XLR

HAND1 602406 Comprehensive Cardiovascular; Congenital Heart Disease

None None

HRAS

190020


109800: {Bladder cancer, somatic} 218040: AD, IC Congenital myopathy with excess of muscle spindles 218040: AD, IC Costello syndrome 162900: {Nevus sebaceous or woolly hair nevus, somatic} 163200: Schimmelpenning-Feuerstein-Mims

syndrome, somatic mosaic 137550: {Spitz nevus or nevus spilus, somatic} 188470: {Thyroid carcinoma, follicular, somatic}

AD, IC

JAG1

601920


118450: AD Alagille syndrome 1 617992: ?Deafness, congenital heart defects, and posterior embryotoxon 187500: AD Tetralogy of Fallot

AD

KRAS

190070


108010: Arteriovenous malformation of the brain, somatic 109800: Bladder cancer, somatic 114480: Breast cancer, somatic 615278: Cardiofaciocutaneous syndrome 2 137215: Gastric cancer, somatic 601626: AD Leukemia, acute myeloid 211980: Lung cancer, somatic 609942: AD Noonan syndrome 3 260350: Pancreatic carcinoma, somatic 614470: AD RAS-associated autoimmune leukoproliferative disorder 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic

AD

LEFTY2 601877 Comprehensive Cardiovascular; Congenital Heart Disease

None None

MAP2K1

176872



None

MAP2K2

601263



None

MED13L

608771


616789: AD Mental retardation and distinctive facial features with or without cardiac defects 608808: AD Transposition of the great arteries, dextro-looped 1

AD

MEIS2 601740 Comprehensive Cardiovascular; Congenital Heart Disease

600987: AD Cleft palate, cardiac defects, and mental retardation

AD

MYH6 160710 Comprehensive Cardiovascular; Comprehensive 614089: Atrial septal defect 3 AD



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Cardiomyopathy; Congenital Heart Disease; Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy

613252: Cardiomyopathy, dilated, 1EE 613251: AD Cardiomyopathy, hypertrophic, 14 614090: {Sick sinus syndrome 3}

NKX2-5

600584


108900: AD Atrial septal defect 7, with or without AV conduction defects 217095: Conotruncal heart malformations, variable 614435: AD Hypoplastic left heart syndrome 2 225250: AD Hypothyroidism, congenital nongoitrous, 5 187500: AD Tetralogy of Fallot 614432: AD Ventricular septal defect 3

AD

NKX2-6 611770 Comprehensive Cardiovascular; Congenital Heart Disease

217095: Conotruncal heart malformations 217095: Persistent truncus arteriosus

None

NODAL 601265 Comprehensive Cardiovascular; Congenital Heart Disease

270100: AD Heterotaxy, visceral, 5 AD

NOTCH1

190198

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies; Congenital Heart Disease


AD

NR2F2 107773 Comprehensive Cardiovascular; Congenital Heart Disease

615779: AD Congenital heart defects, multiple types, 4

AD

NRAS

164790



AD

NSD1 606681 Comprehensive Cardiovascular; Congenital Heart Disease

601626: AD Leukemia, acute myeloid 117550: AD Sotos syndrome 1

AD

PTPN11

176876



AD

RAF1

164760



AD

RIT1

609591



AD

SHOC2

602775



AD

SMAD6 602931 Comprehensive Cardiovascular; Aortopathies; Congenital Heart Disease

614823: AD Aortic valve disease 2 617439: AD {Craniosynostosis 7, susceptibility to}

AD

SOS1

182530


135300: AD ?Fibromatosis, gingival, 1


AD

TBX1

602054


217095: Conotruncal anomaly face syndrome 188400: AD DiGeorge syndrome

187500: AD Tetralogy of Fallot 192430: AD Velocardiofacial syndrome

AD

TBX5 601620 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Congenital Heart Disease

142900: AD Holt-Oram syndrome AD

ZFPM2

603693


610187: Diaphragmatic hernia 3 187500: AD Tetralogy of Fallot 616067: AD 46XY sex reversal 9

AD

ZIC3 300265 Comprehensive Cardiovascular; Congenital Heart Disease

306955: XLR Congenital heart defects, nonsyndromic, 1, XL

XLR, XL



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306955: XLR Heterotaxy, visceral, 1, XL 314390: XLR VACTERL association, XL


Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. GATA6: The following GATA6 hg19 coordinates have been excluded from this assay: chr18:19749269-19749275

3. LEFTY2: The following LEFTY2 hg19 coordinates have been excluded from this assay: chr1:226127049-226127311

4. TBX1: The following TBX1 hg19 coordinates have been excluded from this assay: chr22:19748416-19748814



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FAMILIAL HYPERCHOLESTEROLEMIA (FH) PANEL

Familial hypercholesterolemia (FH) is characterized by elevated plasma levels of low-density lipoprotein (LDL) cholesterol from the time of birth. Commonly, mutations in genes encoding the LDL receptor, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 cause FH. These mutations are inherited in an autosomal dominant manner. In more rare cases, homozygous and compound heterozygosity FH as well as double heterozygosity have been reported. Typically, affected individuals may experience premature cardiovascular events, which may manifest as angina or myocardial infarction and can have an earlier onset in those with homozygous FH. External signs of hypercholesterolemia can also manifest in the form of xanthomata, which can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. Early diagnosis and treatment can reduce morbidity and mortality. The genetic status of at-risk family members can be clarified by molecular genetic testing, especially if the pathogenic variant has been identified in an affected family member, or by measurement of LDL cholesterol concentration.

The Familial Hypercholesterolemia (FH) Panel contains the following 4 genes.


APOB

107730

Comprehensive Cardiovascular; Familial Hypercholesterolemia

144010: AD Hypercholesterolemia, due to ligand-defective apo B 615558: AR Hypobetalipoproteinemia

AD, AR

LDLR 606945 Comprehensive Cardiovascular; Familial Hypercholesterolemia

143890: AD Hypercholesterolemia, familial 143890: AD LDL cholesterol level QTL2

AD

LDLRAP1 605747 Comprehensive Cardiovascular; Familial Hypercholesterolemia

603813: AR Hypercholesterolemia, familial, AR AR

PCSK9

607786 Comprehensive Cardiovascular; Familial Hypercholesterolemia

603776: Hypercholesterolemia, familial, 3

603776: {Low density lipoprotein cholesterol level QTL 1}

None




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PULMONARY HYPERTENSION (PAH) PANEL

Pulmonary arterial hypertension (PAH) is marked by obstruction of the small pulmonary arteries leading to an increase in resistance to blood flow through the lungs. The abnormally elevated pressure in the pulmonary circulation system can lead to progressive heart failure with initial symptoms including dyspnea, fatigue, syncope, chest pain, palpitations, and leg edema. PAH can be heritable in an autosomal dominant form with identical signs and symptoms to PAH of unknown etiology. In some inherited instances, pathogenic variants that disrupt the assembly of bone morphogenetic protein receptors tend to exhibit a more severe phenotype. Continuous intravenous epoprostenol is standard care for individuals with life-threatening PAH. A small minority of individuals respond well to long term oral calcium channel blockers.

The Pulmonary Hypertension Panel contains the following 10 genes.


ACVRL1

601284

Comprehensive Cardiovascular; Hereditary Hemorrhagic Telangiectasia; Pulmonary Hypertension

600376: AD Telangiectasia, hereditary hemorrhagic, type 2

AD

BMPR1B

603248

Comprehensive Cardiovascular; Pulmonary Hypertension

609441: AR Acromesomelic dysplasia, Demirhan type 616849: AD Brachydactyly, type A1, D 112600: AD Brachydactyly, type A2

AD, AR

BMPR2

600799


178600: AD Pulmonary hypertension, familial primary, 1, with or without HHT 178600: AD Pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated 265450: AD Pulmonary venoocclusive disease 1

AD

CAV1

601047


612526: ?Lipodystrophy, congenital generalized, type 3

606721: AD ?Partial lipodystrophy, congenital cataracts, and neurodegeneration syndrome 615343: AD Pulmonary hypertension, primary, 3

AD

EIF2AK4 609280 Comprehensive Cardiovascular; Pulmonary Hypertension

234810: AR Pulmonary venoocclusive disease 2

AR

ENG

131195

Comprehensive Cardiovascular; Hereditary

Hemorrhagic Telangiectasia; Pulmonary Hypertension


AD

GDF2

605120

Comprehensive Cardiovascular; Hereditary Hemorrhagic Telangiectasia; Pulmonary Hypertension


AD

KCNA5

176267



AD

KCNK3 603220 Comprehensive Cardiovascular; Pulmonary Hypertension

615344: AD Pulmonary hypertension, primary, 4

AD

SMAD9 603295 Comprehensive Cardiovascular; Pulmonary Hypertension

615342: AD Pulmonary hypertension, primary, 2 AD




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METABOLIC CARDIOMYOPATHY PANEL

Cardiometabolic syndrome is a constellation of metabolic dysfunction disorders characterized by insulin resistance, impaired glucose tolerance, atherogenic dyslipidemia, hypertension, intra-abdominal adiposity, and an overall clustering of these cardiovascular risk factors. Current approaches to the treatment of cardiometabolic syndrome include control of cardiovascular risk factors with an emphasis on regaining the balance between energy intake and expenditure. The highly heterogeneous nature of cardiometabolic conditions and overlapping phenotypes can challenge clinical assessment. Therefore, targeted gene panels utilizing next-generation sequencing can prove to be effective in prioritizing diagnosis of cardiometabolic conditions and may help distinguish patients who require further investigation.

The Metabolic Cardiomyopathy Panel contains the following 24 genes.


ACADVL

609575

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathy

201475: AR VLCAD deficiency

AR

AGL



AR

ALG1

605907


608540: AR Congenital disorder of glycosylation, type Ik

AR

ALG12

607144 Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Metabolic Cardiomyopathy

607143: AR Congenital disorder of glycosylation, type Ig

AR

ARSB

611542


253200: AR Mucopolysaccharidosis type VI (Maroteaux-Lamy)

AR

CPT2

600650


600649: AR CPT II deficiency, infantile 608836: AR CPT II deficiency, lethal neonatal 255110: AR, AD CPT II deficiency, myopathic, stress-induced 614212: AR, AD {Encephalopathy, acute, infection-induced, 4, susceptibility to}

AD, AR

DOLK

610746


Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Metabolic Cardiomyopathy


AR

FKRP

606596


613153: AR Muscular dystrophy- dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 606612: AR Muscular dystrophy- dystroglycanopathy (congenital with or without mental retardation), type B, 5

607155: AR Muscular dystrophy- dystroglycanopathy (limb-girdle), type C, 5

AR

GAA



AR

GBA

606463


608013: AR Gaucher disease, perinatal lethal 230800: AR Gaucher disease, type I

230900: AR Gaucher disease, type II 231000: AR Gaucher disease, type III 231005: AR Gaucher disease, type IIIC 127750: AD {Lewy body dementia, susceptibility to} 168600: IC, MF {Parkinson disease, late-onset, susceptibility to}

AD, AR, IC,

MF

GBE1

607839


232500: AR Glycogen storage disease IV 263570: AR Polyglucosan body disease, adult form

AR

GLA



XL

GLB1 611458 Comprehensive Cardiovascular; 230500: AR GM1-gangliosidosis, type I AR



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Comprehensive Cardiomyopathy; Metabolic Cardiomyopathy

230600: AR GM1-gangliosidosis, type II 230650: AR GM1-gangliosidosis, type III 253010: AR Mucopolysaccharidosis type IVB (Morquio)

GUSB

611499


253220: AR Mucopolysaccharidosis VII

AR

HADHA

600890


609016: AR Fatty liver, acute, of pregnancy 609016: AR HELLP syndrome, maternal, of pregnancy 609016: AR LCHAD deficiency 609015: AR Trifunctional protein deficiency

AR

HEXB

606873


268800: AR Sandhoff disease, infantile, juvenile, and adult forms

AR

IDUA


607014: AR Mucopolysaccharidosis Ih 607015: AR Mucopolysaccharidosis Ih/s 607016: AR Mucopolysaccharidosis Is

AR

LAMP2

309060



XLD

MTO1

614667



AR

PCCA


606054: AR Propionicacidemia

AR

PCCB

232050


606054: AR Propionicacidemia

AR

SLC22A5

603377

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Dilated Cardiomyopathy; Metabolic Cardiomyopathy


AR

SLC25A20


212138: AR Carnitine-acylcarnitine translocase deficiency

AR

TAZ

300394



XLR


Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive).

2. GBA: The following GBA hg19 coordinates have been excluded from this assay: chr1:155207120-155207380, chr1:155204774-

155204902, chr1:155208296-155208452




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NOONAN SPECTRUM DISORDERS PANEL

Noonan Spectrum Disorders (NSD), or RASopathies, are genetically heterogeneous developmental syndromes caused by heterozygous germline mutations in genes involved in the Ras/MAPK signaling pathway. This pathway is essential for regulation of the cell cycle, cell differentiation, and cellular growth. Noonan Spectrum Disorders occur in 1 in 1,000 to 1 in 2,500 live births. Performing postnatal genetic testing can be clinically useful for individuals that display characteristic features (cardiac abnormalities, specific facial dysmorphisms, developmental delay/intellectual disability, etc.), or prenatally for fetuses that present with certain ultrasound findings (cystic hygroma, increased nuchal translucency, etc.) after a normal chromosome analysis.

The Noonan Spectrum Disorders Panel contains the following 18 genes.


BRAF

164757



AD

CBL

165360



AD, SM

HRAS

190020


109800: {Bladder cancer, somatic} 218040: AD, IC Congenital myopathy with excess of muscle spindles 218040: AD, IC Costello syndrome 162900: {Nevus sebaceous or woolly hair nevus, somatic} 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic

137550: {Spitz nevus or nevus spilus, somatic} 188470: {Thyroid carcinoma, follicular, somatic}

AD, IC

KRAS

190070


108010: Arteriovenous malformation of the brain, somatic 109800: Bladder cancer, somatic 114480: Breast cancer, somatic 615278: Cardiofaciocutaneous syndrome 2 137215: Gastric cancer, somatic 601626: AD Leukemia, acute myeloid 211980: Lung cancer, somatic 609942: AD Noonan syndrome 3 260350: Pancreatic carcinoma, somatic 614470: AD RAS-associated autoimmune leukoproliferative disorder 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic

AD

LZTR1 600574 Noonan Spectrum Disorders 616564: AD Noonan syndrome 10 615670: AD {Schwannomatosis-2, susceptibility to}

AD

MAP2K1

176872



None

MAP2K2

601263



None

NF1

613113

Noonan Spectrum Disorders

607785: AD, SM Leukemia, juvenile myelomonocytic

162210: AD Neurofibromatosis, familial spinal 162200: AD Neurofibromatosis, type 1

AD, SM



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601321: AD Neurofibromatosis-Noonan syndrome 193520: AD Watson syndrome

NRAS

164790



AD

PPP1CB 600590 Noonan Spectrum Disorders 617506: AD Noonan syndrome-like disorder with loose anagen hair 2

AD

PTPN11

176876


151100: AD LEOPARD syndrome 1 607785: Leukemia, juvenile myelomonocytic, somatic

156250: AD Metachondromatosis 163950: AD Noonan syndrome 1

AD

RAF1

164760



AD

RASA2 601589 Noonan Spectrum Disorders None None

RIT1

609591



AD

SHOC2

602775



AD

SOS1

182530


135300: AD ?Fibromatosis, gingival, 1 610733: AD Noonan syndrome 4

AD

SOS2 601247 Noonan Spectrum Disorders 616559: AD Noonan syndrome 9 AD

SPRED1 609291 Noonan Spectrum Disorders 611431: AD Legius syndrome AD


7. RASA2: The following RASA2 hg19 coordinates have been excluded from this assay: chr3:141235158-141235284.



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HEREDITARY HEMORRHAGIC TELANGIECTASIA PANEL

This group comprises genes with cardiac-related disease involvement that cannot be readily classified in the preceding groups that is often part of a constellation of findings associated with syndromic features.

The Hereditary Hemorrhagic Telangiectasia Panel contains the following 5 genes.


ACVRL1

601284

Comprehensive Cardiovascular; Hereditary Hemorrhagic Telangiectasia; Pulmonary

Hypertension


AD

ENG

131195 Comprehensive Cardiovascular; Hereditary

Hemorrhagic Telangiectasia; Pulmonary Hypertension


AD

GDF2

605120

Comprehensive Cardiovascular; Hereditary Hemorrhagic Telangiectasia; Pulmonary

Hypertension


AD

RASA1

139150

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Hereditary

Hemorrhagic Telangiectasia

605462: Basal cell carcinoma, somatic 608354: AD Capillary malformation-

arteriovenous malformation 608355: AD Parkes Weber syndrome

AD

SMAD4

600993

Comprehensive Cardiovascular; Comprehensive Cardiomyopathy; Aortopathies;

Hereditary Hemorrhagic Telangiectasia

175050: AD Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

139210: AD Myhre syndrome 260350: Pancreatic cancer, somatic

174900: AD Polyposis, juvenile intestinal

AD




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References

General References:

1. Pua JC, et al. Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes. J Cardiovasc Transl Res. 2016 Feb;9(1):3-11. 2. Cirino AL, et al. Role of Genetic Testing in Inherited Cardiovascular Disease: A Review. JAMA Cardiol. 2017 Oct 1;2(10):1153-1160. 3. Mital S, et al. Enhancing Literacy in Cardiovascular Genetics: A Scientific Statement From the American Heart Association. Circ Cardiovasc Genet. 2016 Oct;9(5):448-467. 4. Nadar SK and Sandhu K. Genes and Cardiovascular Disease: Where do we go from here? Sultan Qaboos Univ Med J. 2015 Nov;15(4):e448-51. 5. Kathiresan S and Srivastava D. Genetics of human cardiovascular disease. Cell. 2012 Mar 16;148(6):1242-57. 6. Celestino-Soper PB, et al. Validation and Utilization of a Clinical Next-Generation Sequencing Panel for Selected Cardiovascular Disorders. Front Cardiovasc Med. 2017 Mar 15;4:11.

http://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) 7. Lee KA, Williams B, Roza K, Ferguson H, David K, Eddleman K, Stone J, Edelmann L, Richard G, Gelb BD, Kornreich R. PTPN11 analysis for the prenatal diagnosis of Noonan syndrome

in fetuses with abnormal ultrasound findings. Clin Genet. 2009 Feb;75(2):190-4. doi: 10.1111/j.1399-0004.2008.01085.x. Epub 2008 Aug 26. PMID: 18759865 8. Croonen EA, Nillesen WM, Stuurman KE, Oudesluijs G, van de Laar IM, Martens L, Ockeloen C, Mathijssen IB, Schepens M, Ruiterkamp-Versteeg M, Scheffer H, Faas BH, van der

Burgt I, Yntema HG. Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. Eu r J Hum Genet. 2013 Sep;21(9):936-42. doi: 10.1038/ejhg.2012.285. Epub 2013 Jan 16. PMID: 23321623

Gene-Specific References:

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2. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucl er I,Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, PratA, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomaldominant hypercholesterolemia. Nat Genet. 2003 Jun;34(2):154-6. PubMed PMID:12730697.

3. Adegbola A, Musante L, Callewaert B, Maciel P, Hu H, Isidor B, Picker-Minh S, Le Caignec C, Delle Chiaie B, Vanakker O, Menten B, Dheedene A, Bockaert N,Roelens F, Decaestecker K, Silva J, Soares G, Lopes F, Najmabadi H, Kahrizi K,Cox GF, Angus SP, Staropoli JF, Fischer U, Suckow V, Bartsch O, Chess A, RopersHH, Wienker TF, Hübner C, Kaindl AM, Kalscheuer VM. Redefining the MED13Lsyndrome. Eur J Hum Genet. 2015 Oct;23(10):1308-17. doi: 10.1038/ejhg.2015.26.Epub 2015 Mar 11. PubMed PMID: 25758992; PubMed Central PMCID: PMC4592099.

4. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in theglucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2004 Nov 4;351(19):1972- 7. PubMed PMID: 15525722.

5. Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP, Lindsay S,D'Alessandro LC, Swaminathan GJ, Bentham J, Arndt AK, Louw J, Breckpot J,Gewillig M, Thienpont B, Abdul- Khaliq H, Harnack C, Hoff K, Kramer HH, SchubertS, Siebert R, Toka O, Cosgrove C, Watkins H, Lucassen AM, O'Kelly IM, Salmon AP, Bu'lock FA, Granados-Riveron J, Setchfield K, Thornborough C, Brook JD, Mulder B,Klaassen S, Bhattacharya S, Devriendt K, Fitzpatrick DF; UK10K Consortium, WilsonDI, Mital S, Hurles ME. Rare variants in NR2F2 cause congenital heart defects in humans. Am J Hum Genet. 2014 Apr 3;94(4):574-85. doi: 10.1016/j.ajhg.2014.03.007.Erratum in: Am J Hum Genet. 2016 Mar 3;98(3):592. Low, Jacoba [corrected to Louw,Jacoba]. Am J Hum Genet. 2014 Jul 3;95(1):126. PubMed PMID: 24702954; PubMedCentral PMCID: PMC3980509.

6. Aldahmesh MA, Khan AO, Mohamed JY, Alghamdi MH, Alkuraya FS. Identification ofa truncation mutation of acylglycerol kinase (AGK) gene in a novel autosomalrecessive cataract locus. Hum Mutat. 2012 Jun;33(6):960-2. doi:10.1002/humu.22071. Epub 2012 Apr 16. PubMed PMID: 22415731.

7. Almomani R, Verhagen JM, Herkert JC, Brosens E, van Spaendonck-Zwarts KY,Asimaki A, van der Zwaag PA, Frohn-Mulder IM, Bertoli-Avella AM, Boven LG, vanSlegtenhorst MA, van der Smagt JJ, van IJcken WF, Timmer B, van Stuijvenberg M,Verdijk RM, Saffitz JE, du Plessis FA, Michels M, Hofstra RM, Sinke RJ, vanTintelen JP, Wessels MW, Jongbloed JD, van de Laar IM. Biallelic TruncatingMutations in ALPK3 Cause Severe Pediatric Cardiomyopathy. J Am Coll Cardiol. 2016Feb 9;67(5):515-25. doi: 10.1016/j.jacc.2015.10.093. PubMed PMID: 26846950.

8. Anderson SL, Chung WK, Frezzo J, Papp JC, Ekstein J, DiMauro S, Rubin BY. Anovel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family. JInherit Metab Dis. 2008 Dec;31 Suppl 2:S461-7. doi: 10.1007/s10545-008-1049-9.Epub 2008 Dec 26. PubMed PMID: 19107570.

9. Andresen BS, Bross P, Vianey-Saban C, Divry P, Zabot MT, Roe CR, Nada MA,Byskov A, Kruse TA, Neve S, Kristiansen K, Knudsen I, Corydon MJ, Gregersen N.Cloning and characterization of human very-long-chain acyl-CoA dehydrogenasecDNA, chromosomal assignment of the gene and identification in four patients ofnine different mutations within the VLCAD gene. Hum Mol Genet. 1996Apr;5(4):461-72. Erratum in: Hum Mol Genet 1996 Sep;5(9):1390. PubMed PMID:8845838.

10. Antonicka H, Leary SC, Guercin GH, Agar JN, Horvath R, Kennaway NG, HardingCO, Jaksch M, Shoubridge EA. Mutations in COX10 result in a defect inmitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet. 2003 Oct15;12(20):2693-702. Epub 2003 Aug 19. PubMed PMID: 12928484.

11. Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, KennawayNG, Shoubridge EA. Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy. Am JHum Genet. 2003 Jan;72(1):101-14. Epub 2002 Dec 9. PubMed PMID: 12474143; PubMed Central PMCID: PMC378614.

12. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP Jr,Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF,Haïssaguerre M, Schimpf R, Borggrefe M, Wolpert C. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized byST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007 Jan 30;115(4):442-9. Epub 2007 Jan 15. PubMed PMID: 17224476; PubMed CentralPMCID: PMC1952683.

13. Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, TakadaF, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S,Watanabe Y, Ogura T, Matsubara Y. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013 Jul 11;93(1):173-80. doi: 10.1016/j.ajhg.2013.05.021. Epub 2013 Jun 20. PubMed PMID: 23791108; PubMed Central PMCID: PMC3710767.

14. Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, TakadaF, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S,Watanabe Y, Ogura T, Matsubara Y. Gain-of-function mutations in RIT1 cause Noonansyndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013 Jul 11;93(1):173-80. doi: 10.1016/j.ajhg.2013.05.021. Epub 2013 Jun 20. PubMed PMID: 23791108; PubMed Central PMCID: PMC3710767.

15. Arndt AK, Schafer S, Drenckhahn JD, Sabeh MK, Plovie ER, Caliebe A, KlopockiE, Musso G, Werdich AA, Kalwa H, Heinig M, Padera RF, Wassilew K, Bluhm J,Harnack C, Martitz J, Barton PJ, Greutmann M, Berger F, Hubner N, Siebert R,Kramer HH, Cook SA, MacRae CA, Klaassen S. Fine mapping of the 1p36 deletionsyndrome identifies mutation of PRDM16 as a cause of cardiomyopathy. Am J HumGenet. 2013 Jul 11;93(1):67-77. doi: 10.1016/j.ajhg.2013.05.015. Epub 2013 Jun13. PubMed PMID: 23768516; PubMed Central PMCID: PMC3710750.

16. Awad MM, Dalal D, Cho E, Amat-Alarcon N, James C, Tichnell C, Tucker A,Russell SD, Bluemke DA, Dietz HC, Calkins H, Judge DP. DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Hum Genet.2006 Jul;79(1):136-42. Epub 2006 Apr 28. PubMed PMID: 16773573; PubMed CentralPMCID: PMC1474134.

17. Bagnall RD, Yeates L, Semsarian C. Analysis of the Z-disc genes PDLIM3 andMYPN in patients with hypertrophic cardiomyopathy. Int J Cardiol. 2010 Dec3;145(3):601-2. doi: 10.1016/j.ijcard.2010.08.004. PubMed PMID: 20801532.

18. Bao Y, Kishnani P, Wu JY, Chen YT. Hepatic and neuromuscular forms of glycogenstorage disease type IV caused by mutations in the same glycogen-branching enzymegene. J Clin Invest. 1996 Feb 15;97(4):941-8. PubMed PMID: 8613547; PubMedCentral PMCID: PMC507139.

19. Barbier M, Gross MS, Aubart M, Hanna N, Kessler K, Guo DC, Tosolini L,Ho-Tin-Noe B, Regalado E, Varret M, Abifadel M, Milleron O, Odent S, Dupuis-GirodS, Faivre L, Edouard T, Dulac Y, Busa T, Gouya L, Milewicz DM, Jondeau G, BoileauC. MFAP5 loss-of-function mutations underscore the involvement of matrixalteration in the pathogenesis of familial thoracic aortic aneurysms anddissections. Am J Hum Genet. 2014 Dec 4;95(6):736-43. doi:10.1016/j.ajhg.2014.10.018. Epub 2014 Nov 26. PubMed PMID: 25434006; PubMedCentral PMCID: PMC4259978.

20. Barghuti F, Elian K, Gomori JM, Shaag A, Edvardson S, Saada A, Elpeleg O. The unique neuroradiology of complex I deficiency due to NDUFA12L defect. Mol GenetMetab. 2008 May;94(1):78-82. doi: 10.1016/j.ymgme.2007.11.013. Epub 2008 Jan 3.PubMed PMID: 18180188.

21. Baruffini E, Dallabona C, Invernizzi F, Yarham JW, Melchionda L, Blakely EL,Lamantea E, Donnini C, Santra S, Vijayaraghavan S, Roper HP, Burlina A, KopajtichR, Walther A, Strom TM, Haack TB, Prokisch H, Taylor RW, Ferrero I, Zeviani M,Ghezzi D. MTO1 mutations are associated with hypertrophic cardiomyopathy andlactic acidosis and cause respiratory chain deficiency in humans and yeast. HumMutat. 2013 Nov;34(11):1501-9. doi: 10.1002/humu.22393. Epub 2013 Sep 17. PubMed PMID: 23929671; PubMed Central PMCID: PMC4028987.

22. Baskin B, Skinner JR, Sanatani S, Terespolsky D, Krahn AD, Ray PN, Scherer SW,Hamilton RM. TMEM43 mutations associated with arrhythmogenic right ventricularcardiomyopathy in non-Newfoundland populations. Hum Genet. 2013Nov;132(11):1245-52. doi: 10.1007/s00439-013-1323-2. Epub 2013 Jun 29. PubMedPMID: 23812740.


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23. Baumann M, Giunta C, Krabichler B, Rüschendorf F, Zoppi N, Colombi M, Bittner RE, Quijano-Roy S, Muntoni F, Cirak S, Schreiber G, Zou Y, Hu Y, Romero NB,Carlier RY, Amberger A, Deutschmann A, Straub V, Rohrbach M, Steinmann B, RostásyK, Karall D, Bönnemann CG, Zschocke J, Fauth C. Mutations in FKBP14 cause avariant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. Am J Hum Genet. 2012 Feb 10;90(2):201-16. doi:10.1016/j.ajhg.2011.12.004. Epub 2012 Jan 19. PubMed PMID: 22265013; PubMedCentral PMCID: PMC3276673.

24. Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, Bauce B, CarraroG, Thiene G, Towbin JA, Danieli GA, Rampazzo A. Regulatory mutations intransforming growth factor- beta3 gene cause arrhythmogenic right ventricularcardiomyopathy type 1. Cardiovasc Res. 2005 Feb 1;65(2):366-73. PubMed PMID:15639475.

25. Beltran-Valero de Bernabé D, Voit T, Longman C, Steinbrecher A, Straub V, YuvaY, Herrmann R, Sperner J, Korenke C, Diesen C, Dobyns W B, Brunner HG, vanBokhoven H, Brockington M, Muntoni F. Mutations in the FKRP gene can causemuscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet. 2004May;41(5):e61. PubMed PMID: 15121789; PubMed Central PMCID: PMC1735772.

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This test was developed and its performance characteristics were determined by Mount Sinai Genomics, Inc. DBA Sema4 and was considered acceptable for patient testing. It has not been cleared or approved by the FDA. The FDA has determined that such clearance or approval is not necessary. This type of mutation analysis generally provides highly accurate genotype information for microdeletions and microduplications. Despite this level of accuracy, it should be kept in mind that there are many potential sources of diagnostic error, including misidentification of samples, rare polymorphisms, or other rare genetic variants that interfere with analysis. In addition, families should understand the limitations of the testing and that rare diagnostic errors may occur for the reasons described.


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CARDIAC NEXT-GENERATION SEQUENCING PANELS · for Duchenne muscular dystrophy disease (DMD) will only be performed if indicated. For Duchenne muscular dystrophy, the copy numbers of