Overview of Laboratory Genetic

Testing for Rare Diseases and

Conditions

Bin Chen, Ph.D., FACMGAndy Faucett, MS, CGC

Division of Laboratory SystemsPublic Health Practice Program Office

Centers for Disease Control and PreventionMay 20, 2004

Rare Diseases and Conditions NIH ORD (http://rarediseases.info.nih.gov)

Over 6,000 diseases known today ~25 million in US – 1 in every 12 individuals in US

Orphan Drug Act: A disease affecting < 200,000 people in US (prevalence <1/1,465 based on 293 million US population)

Safe Medical Devices Act of 1990 re HUDs: A disease affecting <4,000 individuals in US per year

Orphanet (http://orphanet.infobiogen.fr) 6,000 – 7,000 rare diseases 5 new rare diseases every week in medical literature A disease affecting < 1 per 2,000 people in Europe

Status varies with time and geographic area considered

Rare Diseases and Genetics

GeneTests in 2000 - 751 inherited conditions Prevalence >1/2,000

Clinical: 423 23 (~5%)Research only: 328 18 (~5%)[Ref: Public health impact of genetic tests at the end of the 20th century. Yoon PW. Chen B. Faucett A. Clyne M. Gwinn M. Lubin IM. Burke W. Khoury MJ. Genetics in Medicine. 3(6):405-10, 2001 Nov-Dec]

Most genetic tests currently available are for rare diseases

Most rare diseases are considered genetic conditions

Gene PrevalenceBRCA1 hereditary breast cancer BRCA1 1-2/1,000BRCA2 hereditary breast cancer BRCA2 0.5-1/1,000Cystic Fibrosis CFTR Affected: 1/3,2000

Caucasians (32,000 in US)Carrier: 1/22-28

Caucasians1/61 African Am.1/90 Asian Am.

Factor V Leiden thrombophilia F5 1/5,000 (homozygosity)3-8/100 (Het.)

Familial combined hyperlipidemia APOE 2/1,000Fragile X syndrome FMR1 1/1,250 (males)

1/2,500 (females)Hereditary hemochromatosis HFE 3/1,000

Genetic Tests for ?non-rare Diseases

Current Genetic Tests

GeneTests Apr. 2004

Total Diseases 1,039Clinical 694 (67%)

US 542 (78%)Non US Only 152 (22%)

Research Only 354 (33%) For 1/3 of conditions, testing is available only from

“research” labs For 22% of diseases, clinical testing is available only

outside US

Testing Laboratories

GeneTests Apr. 2004Total Laboratories 598

US 412 (69%)

Clinical 247 (60%)Research Only 165 (40%)

Non US 186 (31%)

“Research only” labs account for 40% of US labs listed in GeneTests

Non US labs account for 31% of all labs listed in the directory

Testing Availability

GeneTests Apr. 2004Total Clinical Testing 694 Diseases

Testing available from only 1 lab 308 (44%)

Testing available from 2-5 labs 224 (32%)

Subtotal 537 (77%)

For >40% diseases, clinical testing is available from only 1 lab For over 70% diseases, testing is available from <5 labs CAP Molecular Genetics Survey: 17 tests EMQN: 13 tests, 1 sequencing

GeneTests Aug. 2003 – Apr. 2004

Changes over past 6 months Changes in clinical testing

New tests Changes in test availability Tests no longer available

Changes in “research only” testing New listing Tests transferred to clinical setting

Snapshots

GeneTests in Past 6 Months

8/2003 4/2004

Total Diseases 996 1,039 (+43)

Clinical 642 693 (+51)

Research Only 354 346 (-8)

GeneTests – Clinical Testing

Changes over past 6 months New Tests: > 51 Tests no longer available: ~10 Tests available from more labs: >30% Tests available from fewer labs: >20

Changes in testing methodology not looked into

Examples: Clinical Tests, Increased Availability

#Labs in 8/2003 4/2004CF 83 92 (+9)Prothrombin G20210A 85 94 (+9)Factor V Leiden 103 110

(+7)Prader-Willi 91 98 (+7)Angelman Syndrome 88 94 (+6)HFE 74 80 (+6)Cxn 26 33 38 (+5)Bloom Syndrome 13 18 (+5)Rett Syndrome 16 21 (+5)MTHFR 67 71 (+4)Fam. Dysautonomia 14 18 (+4)Beta Thalassemia 10 14 (+4)

Examples: Clinical Tests, Increased Availability

#Labs in 8/2003 4/2004Fragile X 99 102 (+3)HNPP 14 18 (+4)CMT 1A 16 20 (+4)CMT 1B 6 9 (+3)SCA 12 3 7 (+4)SCA 8 13 16 (+3)Canavan Disease 34 37 (+3)ARX-related Disorders 1 5 (+4)HNPCC 19 22 (+3)DMD 43 45 (+2)HD 56 58 (+2)

Examples: Clinical Tests, Decreased Availability

#Labs in 8/2003 4/2004BRCA1 19 18 (-1)

BRCA 2 17 16 (-1)

DFNA 9 (COCH) 3 2 (-1)

DFNB 4 5 4 (-1)

Glycogen Storage Disorder IV 3 2 (-1)

Hemoglobin E 6 5 (-1)

Hyperkalemic Periodic Paralysis 1 2 1 (-1)

SCA 7 29 28 (-1)

OTC Def. 15 14 (-1)

Spinal and Bulbar Mus. Atrophy 30 29 (-1)

Examples: Clinical Tests No Longer Available

#Lab in 8/2003 4/2004Amyloidosis Type VI 1 0

DM, noninsulin Dependent 1 0

Episodic Ataxia Type 1 1 (C&R) 0 (R)

Fam. Extraadrenal Pheochromocytoma 1 0

Fam. Hemiplegic Migraine 1 1 0

Nephronophthisis 4 1 (C&R) 0 (R)

*C: Clinical Testing; R: Research Only

Examples: Changes in Clinical Services

#Lab in 8/2003 4/2004Clin. Confirmation for Res. Lab 12 19 (+7)Lab Specimen Matching 12 17 (+5)FISH-Interphase 16 33 (+17)M-FISH/SKY 8 13 (+5)Subtelomeric FISH 27 35 (+8)Y Chromosome Detect. 38 43 (+5)Apo E Genotyping 19 21 (+2)Preimplantation Genetics 0 (8 res. labs) 7 (+7)

Examples: Clinical Testing from Outside US Only

Factor XIII Def. LQT4

MODY I, II, and IV-VI Alzheimer type 1 and 4

Glaucoma, dom. & Rec. Diastrophic dysplasia

Chol. Desmolase def. Nail-Patella Syndrome

Pallister-Hall Syndrome Niemann-Pick Type C1&C2

Usher Syndrome 2A&3 Waardenburg Syndrome type IIA

Wolfram Syndrome …

Examples: Outside US or Research Testing?

Clinical Testing Research OnlyAlport Syndrome 1 Lab in Germany 1 Lab in USAlstrom Syndrome 1 Lab in Portugal 1 Lab in USDeafness-Dystonia-Optic Neuronopathy 1 Lab, Netherlands 1 Lab in NorwayGlaucoma, Dominant 1 Lab in Germany 2 Labs in USGlaucoma, Recessive 1 Lab in Belgium 1 Lab in USMultiple Synostoses Syndrome 1 Lab, Netherlands 1 Lab in USPseudoxanthomaElasticum 1 Lab in Germany 1 Lab in USAchromatopsia 2&3 1 Lab in Germany 2 Labs in USTooth and Nail Syndrome 1 Lab in Belgium 1 Lab in USWalker Warburg Syndrome 1 Lab in Netherlands 1 Lab in US

2 Labs in Germany

GeneTests – Changes in “Research Only” Testing

8/2003 4/2004

Research Only 354 346 (-8)

Tests becoming clinical available: 24

New “research only” tests: 19

Tests removed: >5

GeneTests – April 2004 Changes

New Tests in Clinical Setting: 2 1 added by a clinical lab (3-methylglutaconic Aciduria

Type 3) 1 transferred from research only (Rothmund-Thomson

Syndrome) New Laboratories: 3 (2 clinical, 1 research only) New Disease Category: 1 (SCN5A-related

disorders) Brugada Syndrome, LQT3-related Romano Ward Syndrome Progressive Cardiac Conduction Disease

Total Changes in Listing: 99 Testing methods, contact info, etc Routine update process or at request of laboratories

Summary

Human genome: ~35,000 genes Genes with known sequence as of May 2004:

11,550 New OMIM entries: 60-100 per month Current rare diseases: 6,000 – 7,000 New rare diseases: ~20 per month (5/wk) Diseases for which clinical testing is available:

694 New testing: <10 per month (2 in April 2004)