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Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent.

ABSTRACT: Many recessive genetic disorders are found at a higher incidence in people of Ashkenazi Jewish (AJ) descent than in the general population. The American College of Medical Genetics and the American College of Obstetricians and Gynecologists have recommended that individuals of AJ descent undergo carrier screening for Tay Sachs disease, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia type C, Bloom syndrome, and Gaucher disease. Although these recommendations have led to increased test volumes and number of laboratories offering AJ screening, well-characterized genomic reference materials are not publicly available. The Centers for Disease Control and Prevention-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the genetic testing community and Coriell Cell Repositories, have developed a panel of characterized genomic reference materials for AJ genetic testing. DNA from 31 cell lines, representing many of the common alleles for Tay Sachs disease, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia type C, Bloom syndrome, Gaucher disease, and glycogen storage disease, was prepared by the Repository and tested in six clinical laboratories using three different PCR-based assay platforms. A total of 33 disease alleles was assayed and 25 different alleles were identified. These characterized materials are publicly available from Coriell and may be used for quality control, proficiency testing, test development, and research.

SUBMITTER: Kalman L

PROVIDER: S-EPMC2765751 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent.

Kalman Lisa L Wilson Jean Amos JA Buller Arlene A Dixon John J Edelmann Lisa L Geller Louis L Highsmith William Edward WE Holtegaard Leonard L Kornreich Ruth R Rohlfs Elizabeth M EM Payeur Toby L TL Sellers Tina T Toji Lorraine L Muralidharan Kasinathan K

The Journal of molecular diagnostics : JMD 20091008 6

Many recessive genetic disorders are found at a higher incidence in people of Ashkenazi Jewish (AJ) descent than in the general population. The American College of Medical Genetics and the American College of Obstetricians and Gynecologists have recommended that individuals of AJ descent undergo carrier screening for Tay Sachs disease, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia type C, Bloom syndrome, and Gaucher disease. Although these ...[more]

PMID: 19815695

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Project description:BackgroundTechnological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)-based testing.MethodsIn a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided.ResultsOne thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%.ConclusionCompared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn't adversely affect short-term psychological/quality-of-life outcomes and may detect 56% additional BRCA carriers.

Project description:BackgroundPopulation-based testing for BRCA1/2 mutations detects the high proportion of carriers not identified by cancer family history (FH)-based testing. We compared the cost-effectiveness of population-based BRCA testing with the standard FH-based approach in Ashkenazi Jewish (AJ) women.MethodsA decision-analytic model was developed to compare lifetime costs and effects amongst AJ women in the UK of BRCA founder-mutation testing amongst: 1) all women in the population age 30 years or older and 2) just those with a strong FH (≥10% mutation risk). The model assumes that BRCA carriers are offered risk-reducing salpingo-oophorectomy and annual MRI/mammography screening or risk-reducing mastectomy. Model probabilities utilize the Genetic Cancer Prediction through Population Screening trial/published literature to estimate total costs, effects in terms of quality-adjusted life-years (QALYs), cancer incidence, incremental cost-effectiveness ratio (ICER), and population impact. Costs are reported at 2010 prices. Costs/outcomes were discounted at 3.5%. We used deterministic/probabilistic sensitivity analysis (PSA) to evaluate model uncertainty.ResultsCompared with FH-based testing, population-screening saved 0.090 more life-years and 0.101 more QALYs resulting in 33 days' gain in life expectancy. Population screening was found to be cost saving with a baseline-discounted ICER of -£2079/QALY. Population-based screening lowered ovarian and breast cancer incidence by 0.34% and 0.62%. Assuming 71% testing uptake, this leads to 276 fewer ovarian and 508 fewer breast cancer cases. Overall, reduction in treatment costs led to a discounted cost savings of £3.7 million. Deterministic sensitivity analysis and 94% of simulations on PSA (threshold £20000) indicated that population screening is cost-effective, compared with current NHS policy.ConclusionPopulation-based screening for BRCA mutations is highly cost-effective compared with an FH-based approach in AJ women age 30 years and older.

Dataset Information

Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent.

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Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent.

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