# Presentation: 308204

##  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

- 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		Prevalence
BRCA1 hereditary breast cancer 	BRCA1 	1-2/1,000
BRCA2 hereditary breast cancer  	BRCA2		0.5-1/1,000
Cystic Fibrosis		CFTR		Affected: 1/3,2000 Caucasians 					(32,000 in US)
						Carrier: 1/22-28 Caucasians
								1/61 African Am.
								1/90 Asian Am.
Factor V Leiden thrombophilia	 F5			1/5,000 (homozygosity)
						3-8/100 (Het.)
Familial combined hyperlipidemia	APOE		2/1,000
Fragile X syndrome 		FMR1		1/1,250 (males) 							1/2,500 (females)
Hereditary hemochromatosis 	HFE			3/1,000 

- BRCA1 hereditary breast cancer 	BRCA1 	1-2/1,000
- BRCA2 hereditary breast cancer  	BRCA2		0.5-1/1,000
- Cystic Fibrosis		CFTR		Affected: 1/3,2000 Caucasians 					(32,000 in US)
- 						Carrier: 1/22-28 Caucasians
- 								1/61 African Am.
- 								1/90 Asian Am.
- Factor V Leiden thrombophilia	 F5			1/5,000 (homozygosity)
- 						3-8/100 (Het.)
- Familial combined hyperlipidemia	APOE		2/1,000
- Fragile 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		1,039
- 		Clinical		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. 2004_
- 	Total 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. 2004_
- 	Total 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	4/2004
- CF				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	4/2004
- Fragile 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		4/2004
- BRCA1				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	4/2004
- Amyloidosis 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	4/2004
- Clin. 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 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 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)