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Systematic design and comparison of expanded carrier screening panels.

ABSTRACT: PurposeThe recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.MethodsGuided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.ResultsBased on modeled fetal risks for "severe" and "profound" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen's sensitivity is greatly impacted by two factors: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

SUBMITTER: Beauchamp KA

PROVIDER: S-EPMC5763154 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Systematic design and comparison of expanded carrier screening panels.

Beauchamp Kyle A KA Muzzey Dale D Wong Kenny K KK Hogan Gregory J GJ Karimi Kambiz K Candille Sophie I SI Mehta Nikita N Mar-Heyming Rebecca R Kaseniit K Eerik KE Kang H Peter HP Evans Eric A EA Goldberg James D JD Lazarin Gabriel A GA Haque Imran S IS

Genetics in medicine : official journal of the American College of Medical Genetics 20170622 1

PurposeThe recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.MethodsGuided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendeli ...[more]

PMID: 28640244

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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

Systematic design and comparison of expanded carrier screening panels.

Publications

Systematic design and comparison of expanded carrier screening panels.

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