Autosomal recessive disease risk in offspring of qualified sperm bank donors and clients: proof of principle for a novel analysis based on virtual progeny

Lim, Regine M.; Silver, Ari J.; Borroto, Carlos; Spurrier, Brett; Silver, Rachel E; Remis, A.B.; Cohn, A.S.; Morriss, Anne; Silver, Lee M.

doi:10.1016/j.fertnstert.2014.07.1039

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“…Despite tremendous advances in variant identification, understanding, and analysis, the vast majority of disease-causing mutation combinations remain undetected in the carrier screening process. Most important, the exposure of recipient offspring to recessive disease risk is not reduced sufficiently by this protocol (Lim et al , 2014 ). To achieve the ultimate screening goal of protecting future children from highly heritable disease, industry screening standards must be modernized to reflect the biological reality that both donors and recipients carry a wide range of known and novel disease-causing variants that cause a spectrum of damage to the underlying gene.…”

Section: Discussionmentioning

confidence: 99%

Carrier Screening is a Deficient Strategy for Determining Sperm Donor Eligibility and Reducing Risk of Disease in Recipient Children

Silver¹,

Larson²,

Silver³

et al. 2016

Genetic Testing and Molecular Biomarkers

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Aims: DNA-based carrier screening is a standard component of donor eligibility protocols practiced by U.S. sperm banks. Applicants who test positive for carrying a recessive disease mutation are typically disqualified. The aim of our study was to examine the utility of a range of screening panels adopted by the industry and the effectiveness of the screening paradigm in reducing a future child's risk of inheriting disease. Methods: A cohort of 27 donor applicants, who tested negative on an initial cystic fibrosis carrier test, was further screened with three expanded commercial carrier testing panels. These results were then compared to a systematic analysis of the applicants' DNA using next-generation sequencing (NGS) data. Results: The carrier panels detected serious pediatric disease mutations in one, four, or six donor applicants. Because each panel screens distinct regions of the genome, no single donor was uniformly identified as carrier positive by all three panels. In contrast, systematic NGS analysis identified all donors as carriers of one or more mutations associated with severe monogenic pediatric disease. These included 30 variants classified as “pathogenic” based on clinical observation and 66 with a high likelihood of causing gene dysfunction. Conclusion: Despite tremendous advances in variant identification, understanding, and analysis, the vast majority of disease-causing mutation combinations remain undetected by commercial carrier screening panels, which cover a narrow, and often distinct, subset of genes and mutations. The biological reality is that all donors and recipients carry serious recessive disease mutations. This challenges the utility of any screening protocol that anchors donor eligibility to carrier status. A more effective approach to reducing recessive disease risk would consider joint comprehensive analysis of both donor and recipient disease mutations. This type of high-resolution recessive disease risk analysis is now available and affordable, but industry practice must be modified to incorporate its use.

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Section: Discussionmentioning

confidence: 99%