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Come gather 'round people Wherever you roam And admit that the waters Around you have grown And accept it that soon You'll be drenched to the bone. If your time to you Is worth savin' Then you better start swimmin' Or you'll sink like a stone For the times they are a-changin'. - PowerPoint PPT Presentation
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Come gather 'round peopleWherever you roamAnd admit that the watersAround you have grownAnd accept it that soonYou'll be drenched to the bone.If your time to youIs worth savin'Then you better start swimmin'Or you'll sink like a stoneFor the times they are a-changin'.
THE NEXT GENERATION:Microarray and Beyond
Karyotype
Resolution: >7-10 Million Base Pairs
(7-10 Mb)
Resolution: < 0.5 Million Base Pairs
(< 500 kb)
Chromosomal Microarray(CMA)
Microdeletion Syndromes
DiGeorge 22q11 Deletion 3.5Mb
Miller Dieker 17p13.3 deletionPrader Willi 15q11-13 deletion 4MBSmith Magenis
17p11.2 deletion 5Mb
Wolf Hirshhorn
4p16.3 deletion 1.9Mb
Williams-Beuren
7q11.23Deletion 1.5Mb
Non-Syndromic Micro Del /Dups
15-20% yield by CMA in children with unexplained developmental delay/ID, and congenital anomalies compared to ~3% with karyotype
16p11.2 Autism 0.55Mb
1q21.1 ID, microcephaly, cardiac, cataracts
0.8Mb
16p13.11 Autism, ID, and schizophrenia
0.8Mb
ID: Intellectual Disability
Velo Cardio Facial Syndrome
Postnatal Studies
Structural Anomalies
Array Adds Significant Clinically Relevant Information in Cases With Normal Karyotype
Structural Anomaly Fiorentino 6.1 %Rosenfeld /Shaffer 6.6 %Schwartz 5.7 %NICHD 6.0 %
7q11.23 microduplication syndrome
Amniocentesis:Karyotype: 46,XYArray: 1.39 Mb gain in 7q11.23
Van der Aa, et al. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. European Journal of Medical Genetics 2009
Left Foot Right Foot
Differential Diagnosis• Aase Syndrome• Diamond-blackfan Syndrome• DOOR Syndrome• Duane-radial Syndrome (DR Syndrome)• Fanconi Anemia (Pancytopenia-dysmelia Syndrome)• Fetal Hydantoin Syndrome (Dilantin Embryopathy)• Goodman Syndrome• Holt-Oram Syndrome• Hypomelanosis Of Ito• IVIC Syndrome• Juberg-hayward Syndrome• Lacrimo-auriculo-dento-digital Syndrome (LADD Syndrome) (Levy-hollister Syndrome)• Mesomelic Dysplasia (Werner Type)• Nager Syndrome• Normal Variant : Isolated Anomaly• Poland Syndrome (Pectoral Muscle Aplasia-syndactyly)• Thalidomide Embryopathy• Townes-brocks Syndrome• Trichorhinophalangeal Dysplasia Type (Langer Gidieon Syndrome)• Trisomy 13• Trisomy 22• VATER Association
Mutation
Sequencing
Triphalangeal thumb with Polysyndactyly
• Mutation in SHH gene
• Mutations in the Sonic hedgehog limb enhancer, the zone of polarizing activity regulatory sequence (ZRS, located within the gene LMBR1), commonly called the ZRS), cause limb malformations
Sequencing Analysis
You’re pregnant andYou must know the sex Deep sequencing Ma,
It’s all the rage !
BH 2012 SC
By Indications for Testing
Indication Total Clinically Relevant
95% CI
AMAN=1966
34 (1.7%) 1.2 – 2.4
Positive ScreenN=729
12(1.6%) 0.9 – 2.9
Clinically Relevant Information Seen by CMA andReported to Patients in Cases with
Normal Karyotype
Recurrent CNVs That Have The Potential To Cause Neurocognitive Impairment
Occurred in approximately 1 in 125 (0.8%) cases sampled for AMA or positive screening
Deletions N Nl US1q21.17q11.23
11
10
15q11.2 2 215q13.2q13.3 1 116p11.2 3 216p12.1 1 016p13.11p12.3 3 116p13.11 5 317q12 6 122q11.2 11 3
Duplications N Nl US
1q21.115q11.2q13.115q13.2q13.3
411
211
16p13.11p12.3 2 116p13.11 4 317q1222q11.21
32
22
Conclusion
Based on the increased detection of clinically relevant abnormalities in both structurally normal and abnormal pregnancies, chromosomal microarray analysis (CMA) should be transitioned to become the first tier test for invasive prenatal cytogenetic diagnosis.
Findings of Unknown Significance
Variable Expressivity
Variants of Uncertain Clinical Significance
1. Other Cases - known del/dup or Mendelian disorders
OMIM, DECIPHER (Sanger)- known benign CNV
DGV (Toronto), dbVar (NCBI)- comparison with other cases
PubMed, DECIPHER2. Large Databases
ISCAConsortium3. Genomic/Gene Content
- correlates with size/locationUCSC, Ensembl (Sanger)
Variants Of Uncertain Clinical Significance
Counseling Issues
VOUS Pathogenic Likely Benign
2007 Study Classification
94(2.5%)
35(0.9%) -
2012 Classification
57(1.5%)
64(1.7%)
8
As CMA Transitions Into Practice Counseling By Professionals With Knowledge And Expertise In CMA Will Be Required
Mosaic Inversion Balanced Recip Translocation
Marker Other Autosmeal Trisomy
Total
Han 2008 .15 % .15% .50 % .10% .02% .85 %
Chang2012 .3 % .20 % .40% .08% - 1.0 %
Frequency of Findings of Uncertain Significance in Amniocentesis Karyotype
CVS: Confined Placental Mosaicism 1-2%
Berg: Genetics in Medicine 2011
Berg, Genetics In Medicine, June 2011
?
CVS: del16p13.12p13.11
CVS: del16p13.12p13.11 CVS: 2.0 Mb del16p13.12p13.11
Described with Autism Spectrum Disorder (ASD)/Developmental Delay, and seizures
Incomplete penetrance/ Variable Expressivity
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85-89
90-94
95-99
100-104
105-109
110-114
115-119
120-124
125-129
130-134
135-139
140-144
0
2
4
6
8
10
12
14
16
18
20
ControlCarrier
Num
ber o
f Cas
esFull Scale IQ difference of 28 or 2 SD
Mean 80SD 15
Mean 108SD 12
Counseling Issues
Long term prospective study of individuals identified with pathogenic CNVs and variants of
uncertain clinical significance
Incomplete Penetrance/ Variable Expressivity
Non Invasive Prenatal Diagnosis of Common Trisomies (13,18,21)
( 1:500 Pregnancies)
Vs
Invasive Diagnosis with Array Analysis(>1:100)
All Patients Should be Counseled about the Relative Advantages and Disadvantages of Each Approach
PRETEST COUNSELING
• Additional information about the health/development of the child
• Findings of uncertain significance• Unanticipated information about the health of a parent• Pre-symptomatic recognition of adult on-set condition• Determination of non-paternity
Should be discussed with the patient prior to testing and an understanding of the patients interest in this information should be explored and documented
Issues To Discuss
Who will/can do this?
Noninvasive Prenatal Diagnosis of a Fetal MicrodeletionSyndrome
David Peters, Ph.D.Tianjiao Chu, Ph.D.Svetlana A. Yatsenko, M.D.Nancy Hendrix, M.D.W. Allen Hogge,M.D. UrvashiSurti, Ph.D. Kimberly Bunce, Ph.D.Mary Dunkel, M.S.Patricia ShawB.S.AleksandarRajkovic, M.D.Magee–Womens Research Institute
GENOMICSNoninvasive Whole-Genome Sequencing of a Human FetusJacob O. Kitzman,1 * Matthew W. Snyder,1 Mario Ventura,1,2 Alexandra P. Lewis,1 Ruolan Qiu,1LaVone E. Simmons,3 Hilary S. Gammill,3,4 Craig E. Rubens,5,6 Donna A. Santillan,7Jeffrey C. Murray,8 Holly K. Tabor,5,9 Michael J. Bamshad,1,5 Evan E. Eichler,1,10 Jay Shendure1 *
Concerns of Increasingly Complex Non-Invasive Fetal Testing
• Uncertain Reassurance• More Uncertain Findings• Scope Creep• Counseling • Ethics of What to Test For