NEW YORK & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Comparative analysis of sperm donor applicants using three commercial carrier tests and a comprehensive assessment of next generation sequencing (NGS) data demonstrates the failure of carrier screening to detect the vast majority of genetic mutations that can cause severe, recessive diseases in children. The findings, by a GenePeeks research team led by Lee M. Silver, Ph.D., are published in the June 2016 issue of Genetic Testing and Molecular Biomarkers (available online at http://online.liebertpub.com/doi/full/10.1089/gtmb.2016.0014).
The study conducted by GenePeeks, Inc., a genetic information company focused on preconception genetic risk determination, spotlights the need to overhaul screening protocols to take advantage of the tremendous advances in human genomics that have occurred over the past decade. The study highlights the fact that all human beings – including all sperm donors -- carry serious recessive disease mutations, most of which go undetected by commercial carrier screening panels.
According to Genetic Testing and Molecular Biomarkers Editor-in-Chief Garth D. Ehrlich, “Silver et al have demonstrated that – among other important findings -- current sperm bank testing gives prospective parents a false sense of security.”
Carrier screening involves analysis of prospective parents’ carrier status to determine whether they carry any of a predetermined list of genetic mutations. However, the study shows that the existing focus on a relatively small number of historically observed “knock-out” mutations means that the vast majority of disease-causing mutations are not observed in the carrier screening process.
“Our analysis identifies a range of serious deficiencies in the methods currently used to screen for disease risk, including the low sensitivity of carrier tests and the limitations of focusing on a single member of a reproductive pair – in this case, a sperm donor, ” said Lee M. Silver, Ph.D., Co-founder of GenePeeks, Inc. and Professor of Molecular Biology at Princeton University. “Any effective strategy for protecting families must include comprehensive, combined analysis of both parental genomes.”
Study Methodology
For this study, researchers assembled a cohort of 27 sperm donor applicants who had tested negative on an initial screen for 92 mutations in the gene associated with cystic fibrosis. The cystic fibrosis test is often used as part of the qualification process at U.S. sperm banks.
The GenePeeks team then evaluated these same donors with three expanded commercial testing panels that some sperm banks use as an additional layer of qualification. These included the GeneVu panel from Good Start Genetics, the Family Prep Screen 1.0 from Counsyl, and the Personal Genome Service from 23andMe, which each target a different list of genes and mutations. The researchers compared test results to a systematic analysis of 450 recessive disease genes based on next generation sequencing (NGS) of two million basepairs of DNA in each donor genome.
Summary of Results: Severe, Recessive Disease Mutations Carried by 27 Sperm Donor Applicants:
| Gene | Good Start Genetics: 6 carriers | 23andMe: 1 carrier | Counsyl: 4 carriers | Systematic Next Gen Sequencing Analysis: 27 carriers | ||||||||
| GBA | Gaucher Disease | Gaucher disease | Gaucher Disease | |||||||||
| BMS | Bloom Syndrome | Bloom Syndrome | ||||||||||
| SMN1 | Spinal Muscular Atrophy | Spinal Muscular Atrophy | ||||||||||
| HBA1 | Alpha Thalassemia | Alpha Thalassemia | ||||||||||
| ACADM | MCAD deficiency | MCAD deficiency | MCAD deficiency | |||||||||
| IDUA | mucopolysaccharidosis | mucopolysaccharidosis | ||||||||||
| DHCR7 | Smith-Lemli-Opitz syndrome | Smith-Lemli-Opitz syndrome | ||||||||||
| PYGM | McArdle disease | McArdle disease | ||||||||||
| 89 additional mutations not found by carrier tests surveyed in the study. | ||||||||||||
Key Takeaways
- All sperm donors – like all human beings -- carry serious disease-causing mutations. Systematic analysis of NGS data revealed that all 27 subjects carried one or more highly damaging gene variants associated with severe recessive pediatric disease. These included 30 variants classified as “pathogenic” based on clinical observation and 66 with a high likelihood of causing gene dysfunction based on well-established protocols for evaluating novel gene dysfunction.
- Carrier testing panels only detect a small fraction of disease-causing mutations. Despite the universal presence of serious, disease-causing mutations in all 27 research subjects, commercial carrier panels only detected 9 subjects to be carrier-positive and identified just 6% of the mutations present in the cohort. And because each carrier test screened different regions of the genome, no single subject was uniformly identified to be a carrier by all three panels.
- Carrier testing panels do not assess whole categories of disease-causing mutations, including most novel and partial-function mutations. High-resolution analysis of subjects’ sequence data revealed that 2/3 of the mutations found were novel, a finding consistent with population studies and the principles of modern genetics. In addition, researchers identified a number of mutations that only partially reduced gene function but are known to contribute to serious diseases. Based on the industry’s current definition of a carrier, individuals harboring these partial-function mutations would not be considered carriers. However, each of these mutations unambiguously contributes to disease when combined with a more dysfunctional mutation carried by a reproductive partner.
“This study makes it clear that we can make enormous improvements in the way we protect children from disease risk,” said Anne Morriss, CEO of GenePeeks. “Screening donors for a few, well-known variants is no longer good enough.”
About GenePeeks
GenePeeks is a genetic information company focused on identifying inherited disease risk in future generations. GenePeeks’ patented technology digitally combines the genetic information of two potential parents, simulating the complex genetic interactions that occur naturally in human reproduction. The company’s proprietary platform creates and analyzes thousands of Virtual Progeny to uncover disease risk that cannot be seen with alternative screening tools.
Using its patented platform, GenePeeks has developed a safe, non-invasive process for helping sperm and egg bank clients avoid donor matches that carry a high risk of passing on severe pediatric diseases. GenePeeks is now developing services for any family planning a pregnancy and using its expertise to conduct research to advance understanding of genetic disease and the effectiveness of pre-pregnancy risk prediction.
GenePeeks was founded by CEO Anne Morriss and Lee Silver, Ph.D., Professor of Molecular Biology at Princeton University, to help families protect their future children from serious diseases. The company’s Executive Chair is Mara Aspinall, former CEO of Ventana Health Systems and former President of Genzyme Genetics. GenePeeks is privately held by Lifeprint Group, with offices in New York and Cambridge, Mass. For more information, visit www.genepeeks.com.
