Lessons learned from expanded reproductive carrier screening in self-reported Ashkenazi, Sephardi, and Mizrahi Jewish patients

Abstract

Background: Next-generation sequencing (NGS)-based panels have gained traction as a strategy for reproductive carrier screening. Their value for screening Ashkenazi Jewish (AJ) individuals, who have benefited greatly from population-wide targeted testing, as well as Sephardi/Mizrahi Jewish (SMJ) individuals (an underserved population), has not been fully explored.

Methods: The clinical utilization by 6,805 self-reported Jewish individuals of an expanded NGS panel, along with several ancillary assays, was assessed retrospectively. Data were extracted for a subset of 96 diseases that, during the panel design phase, were classified as being AJ-, SMJ-, or pan-Jewish/pan-ethnic-relevant.

Results: 64.6% of individuals were identified as carriers of one or more of these 96 diseases. Over 80% of the reported variants would have been missed by following recommended AJ screening guidelines. 10.7% of variants reported for AJs were in "SMJ-relevant genes," and 31.2% reported for SMJs were in "AJ-relevant genes." Roughly 2.5% of individuals carried a novel, likely pathogenic variant. One in 16 linked cohort couples was identified as a carrier couple for at least one of these 96 diseases.

Conclusion: For maximal carrier identification, this study supports using expanded NGS panels for individuals of all Jewish backgrounds. This approach can better empower at-risk couples for reproductive decision making.

Keywords: Ashkenazi Jewish; Sephardi/Mizrahi Jewish; carrier couple; expanded carrier screening; preconception/prenatal genetic testing.

Figure 1

Overview of testing performed for self‐reported Jewish individuals. ^†Those with an indication other than routine carrier screening have been excluded, albeit that some individuals may have had (more limited) carrier screening previously. ^‡The genotyping panel of 38 is that described in (Shi et al., 2017) with the addition of SMA/FXS testing. The panel of 96 is described in the text and shown in Table S3; subpanels of that included 48 SMJ + pan‐ethnic/pan‐Jewish diseases or 58 AJ + pan‐ethnic/pan‐Jewish diseases. Larger panels (of 252–281 diseases) included the full 96‐disease set. ^§Carrier is defined as someone carrying one or more reported pathogenic/likely pathogenic variants in any of the 96 genes as detected by NGS (or genotyping analysis for certain variants [see methods in Supporting Information]). Abbreviations: M, males; F, females

Figure 2

Increased detection rates with panel expansion. Each bar represents the breakdown of the three categories (labeled on x‐axis) for a given testing panel (y‐axis) relative to the total number of reported “variants detected” when the 96 disease gene set of the NGS panel is used for AJs (top) or SMJs (bottom), each of which is taken to be 100%. The genotyping panel of 36 diseases is described in Shi et al. (2017), and the genotyping panel of nine diseases includes CF plus the eight ACMG diseases (Gross et al., 2008). NGS panels of 48 and 58 are described in the text; both exclude SMA and FXS carriers that are detected by other means. Abbreviations: AJ, Ashkenazi Jewish; SMJ, Sephardi/Mizrahi Jewish

Figure 3

Overview of results from TSD screening. DNA (a) and enzyme (b) testing results are shown. DNA carriers do not include those with pseudodeficiency alleles. Abbreviations: AJ, Ashkenazi Jewish; NGS, next‐generation sequencing

Figure 4

Characteristics of carrier couples for autosomal recessive diseases. (a) Distribution of Jewish subethnicities of identified couples wherein both members were carriers for the same genetic disorder among the set of 96 genes. (b) Distribution of these carrier couples by penetrance of their allelic combinations. The number of couples who were carriers for a given gene is shown in parentheses. CFTR and GJB2 fall into both groups, depending on the specific variants detected. (c) Pregnancy status of the identified carrier couples at the time of testing. Abbreviations: AJ, Ashkenazi Jewish; OJ, Other Jewish; SMJ, Sephardi/Mizrahi Jewish