Overview of Laboratory Genetic Testing for Rare Diseases

Overview of Laboratory Genetic Testing for Rare Diseases and Conditions Bin Chen, Ph. D. , FACMG Andy Faucett, MS, CGC Division of Laboratory Systems Public Health Practice Program Office Centers for Disease Control and Prevention May 20, 2004

Rare Diseases and Conditions n n n NIH ORD (http: //rarediseases. info. nih. gov) n Over 6, 000 diseases known today n ~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) n 6, 000 – 7, 000 rare diseases n 5 new rare diseases every week in medical literature n A disease affecting < 1 per 2, 000 people in Europe Status varies with time and geographic area considered

Rare Diseases and Genetics n Gene. Tests in 2000 - 751 inherited conditions Clinical: 423 Research only: 328 Prevalence >1/2, 000 23 (~5%) 18 (~5%) [Ref: Public health impact of genetic tests at the end of the 20 th 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] n n Most genetic tests currently available are for rare diseases Most rare diseases are considered genetic conditions

Genetic Tests for ? non-rare Diseases Gene BRCA 1 hereditary breast cancer BRCA 2 hereditary breast cancer Cystic Fibrosis CFTR Am. Factor V Leiden thrombophilia (homozygosity) Familial combined hyperlipidemia Fragile X syndrome Prevalence BRCA 1 1 -2/1, 000 BRCA 2 0. 5 -1/1, 000 Affected: 1/3, 2000 Caucasians (32, 000 in US) Carrier: 1/22 -28 Caucasians 1/61 African 1/90 Asian F 5 APOE FMR 1 1/5, 000 3 -8/100 (Het. ) 2/1, 000 1/1, 250 (males)

Current Genetic Tests Gene. Tests Apr. 2004 Total Diseases Clinical US 542 Non US Only Research Only n n 1, 039 694 (67%) (78%) 152 (22%) 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 Gene. Tests Apr. 2004 Total Laboratories US 598 412 (69%) Clinical 247 (60%) Research Only 165 (40%) Non US n n 186 (31%) “Research only” labs account for 40% of US labs listed in Gene. Tests Non US labs account for 31% of all labs listed in the directory

Testing Availability Gene. Tests Apr. 2004 Total Clinical Testing available from only 1 lab 308 (44%) Testing available from 2 -5 labs 224 (32%) Subtotal § § 694 Diseases 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

Gene. Tests Aug. 2003 – Apr. 2004 § Changes over past 6 months § Changes in clinical testing Ø New tests Ø Changes in test availability Ø Tests no longer available § Changes in “research only” testing Ø New listing Ø Tests transferred to clinical setting § Snapshots

Gene. Tests in Past 6 Months 8/2003 Total Diseases Clinical Research Only 4/2004 996 642 1, 039 (+43) 693 (+51) 354 346 (-8)

Gene. Tests – 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 CF 83 Prothrombin G 20210 A Factor V Leiden Prader-Willi Angelman Syndrome HFE 74 Cxn 26 33 Bloom Syndrome Rett Syndrome MTHFR 67 Fam. Dysautonomia Beta Thalassemia 4/2004 103 91 16 92 (+9) 85 88 80 (+6) 38 (+5) 13 71 (+4) 14 10 94 (+9) 110 (+7) 98 (+7) 94 (+6) 21 (+5) 18 (+4) 14 (+4)

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

Examples: Clinical Tests, Decreased Availability #Labs in 8/2003 BRCA 1 BRCA 2 DFNA 9 (COCH) DFNB 4 Glycogen Storage Disorder IV Hemoglobin E Hyperkalemic Periodic Paralysis 1 SCA 7 OTC Def. Spinal and Bulbar Mus. Atrophy 19 17 3 5 3 6 2 29 15 30 4/2004 18 (-1) 16 (-1) 2 (-1) 4 (-1) 2 (-1) 5 (-1) 1 (-1) 28 (-1) 14 (-1) 29 (-1)

Examples: Clinical Tests No Longer Available #Lab in 8/2003 4/2004 Amyloidosis Type VI 0 1 DM, noninsulin Dependent 0 Episodic Ataxia Type 1 0 (R) 1 1 (C&R) Fam. Extraadrenal Pheochromocytoma 1 0 Fam. Hemiplegic Migraine 1 0 Nephronophthisis 4 0 (R) 1 1 (C&R)

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

Examples: Clinical Testing from Outside US Only Factor XIII Def. LQT 4 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 C 1&C 2 Usher Syndrome 2 A&3 Waardenburg Syndrome type IIA Wolfram Syndrome …

Examples: Outside US or Research Testing? Clinical Testing Research Only Alport Syndrome 1 Lab in Germany 1 Lab in US Alstrom Syndrome 1 Lab in Portugal 1 Lab in US Deafness-Dystonia. Optic Neuronopathy 1 Lab, Netherlands 1 Lab in Norway Glaucoma, Dominant 1 Lab in Germany 2 Labs in US Glaucoma, Recessive 1 Lab in Belgium 1 Lab in US Multiple Synostoses Syndrome 1 Lab, Netherlands 1 Lab in US Pseudoxanthoma Elasticum 1 Lab in Germany 1 Lab in US Achromatopsia 2&3 1 Lab in Germany 2 Labs in US Tooth and Nail Syndrome 1 Lab in Belgium 1 Lab in US Walker Warburg Syndrome 1 Lab in Netherlands 1 Lab

Gene. Tests – Changes in “Research Only” Testing Research Only 8/2003 4/2004 354 346 (-8) § Tests becoming clinical available: 24 § New “research only” tests: 19 § Tests removed: >5

Gene. Tests – April 2004 Changes n New Tests in Clinical Setting: 2 n n New Laboratories: 3 (2 clinical, 1 research only) New Disease Category: 1 (SCN 5 A-related disorders) n n 1 added by a clinical lab (3 -methylglutaconic Aciduria Type 3) 1 transferred from research only (Rothmund-Thomson Syndrome) Brugada Syndrome, LQT 3 -related Romano Ward Syndrome Progressive Cardiac Conduction Disease Total Changes in Listing: 99 n n Testing methods, contact info, etc Routine update process or at request of laboratories

Summary n n n n 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)