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Clinical validity of expanded carrier screening: Evaluating the gene-disease relationship in more than 200 conditions.

ABSTRACT: Clinical guidelines consider expanded carrier screening (ECS) to be an acceptable method of carrier screening. However, broader guideline support and payer adoption require evidence for associations between the genes on ECS panels and the conditions for which they aim to identify carriers. We applied a standardized framework for evaluation of gene-disease association to assess the clinical validity of conditions screened by ECS panels. The Clinical Genome Resource (ClinGen) gene curation framework was used to assess genetic and experimental evidence of associations between 208 genes and conditions screened on two commercial ECS panels. Twenty-one conditions were previously classified by ClinGen, and the remaining 187 were evaluated by curation teams at two laboratories. To ensure consistent application of the framework across the laboratories, concordance was evaluated on a subset of conditions. All 208 evaluated conditions met the evidence threshold for supporting a gene-disease association. Furthermore, 203 of 208 (98%) achieved the strongest ("Definitive") level of gene-disease association. All conditions evaluated by both commercial laboratories were similarly classified. Assessment using the ClinGen standardized framework revealed strong evidence of gene-disease association for conditions on two ECS panels. This result establishes the disease-level clinical validity of the panels considered herein.

SUBMITTER: Balzotti M

PROVIDER: S-EPMC7496796 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Clinical validity of expanded carrier screening: Evaluating the gene-disease relationship in more than 200 conditions.

Balzotti Marie M Meng Linyan L Muzzey Dale D Johansen Taber Katherine K Beauchamp Kyle K Curation Team Myriad Genetics MG Curation Team Baylor Genetics BG Mar-Heyming Rebecca R Buckley Bethany B Moyer Krista K

Human mutation 20200521 8

Clinical guidelines consider expanded carrier screening (ECS) to be an acceptable method of carrier screening. However, broader guideline support and payer adoption require evidence for associations between the genes on ECS panels and the conditions for which they aim to identify carriers. We applied a standardized framework for evaluation of gene-disease association to assess the clinical validity of conditions screened by ECS panels. The Clinical Genome Resource (ClinGen) gene curation framewo ...[more]

PMID: 32383249

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Project description:Study questionWhat are the sperm and egg donor rejection rates after expanded carrier screening (ECS)?Summary answerUsing an ECS panel looking at 46/47 genes, 17.6% of donors were rejected.What is known alreadyThe use of ECS is becoming commonplace in assisted reproductive technology, including testing of egg and sperm donors. Most national guidelines recommend rejection of donors if they are carriers of a genetic disease. If the use of ECS increases, there will be a decline in the number of donors available.Study design, size, durationA review of the current preconception ECS panels available to donors was carried out through an online search. The genetic testing results of donors from Cryos International were analysed to determine how many were rejected on the basis of the ECS.Participants/materials, setting, methodsData on gamete donors and their carrier status was provided by Cryos International, who screen donors using their own bespoke ECS panel. The ECS panels identified through the review were compared to the Cryos International panel and data.Main results and the role of chanceA total of 16 companies and 42 associated ECS panels were reviewed. There were a total of 2673 unique disorders covered by the panels examined, with a mean of 329 disorders screened. None of these disorders were common to all panels. Cryos International screen 46 disorders in males and 47 in females. From 883 candidate donors, 17.6% (155/883) were rejected based on their ECS result. Carriers of alpha-thalassaemia represented the largest proportion of those rejected (19.4%, 30/155), then spinal muscular atrophy (15.5%, 24/155) and cystic fibrosis (14.8%, 23/155).Limitations, reasons for cautionPanel information was found on company websites and may not have been accurate.Wider implications of the findingsThis study highlights the need for consistent EU regulations and guidelines that allow genetic matching of gamete donors to their recipients, preventing the need to reject donors who are known carriers. A larger ECS panel would be most beneficial; however, this would not be viable without matching of donors and recipients.Study funding/competing interest(s)No specific funding was obtained. J.C.H. is the founder of Global Women Connected, a platform to discuss women's health issues and the Embryology and PGD Academy, who deliver education in clinical embryology. She has been paid to give a lecture by Cryos in 2019. A-B.S. is an employee of Cryos International.Trial registration numberN/A.

Dataset Information

Clinical validity of expanded carrier screening: Evaluating the gene-disease relationship in more than 200 conditions.

Publications

Clinical validity of expanded carrier screening: Evaluating the gene-disease relationship in more than 200 conditions.

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