Pathogenic variant‐based preconception carrier screening in the Israeli Jewish population

Abstract

Preconception carrier screening allows identification of couples at risk to have offspring with autosomal recessive and X‐linked disorders. In a current multiethnic world, screening based on self‐reported ancestry has limitations. Here we describe the findings of a comprehensive pan‐ethnic variant‐based carrier screening, using the Israeli Jewish population as a model. The cohort included 1696 individuals (848 couples) tested with the ‘MyScreen’ multigene panel. The panel covers 1206 variants spanning 385 genes, known in different Jewish ethnicities and local Arab, Druze and Bedouin populations. Out of these, 205 variants in 143 genes are Jewish founder variants. We identified 859 (50.6%), carriers of at least one variant in 151 genes. Importantly, 569 (66.2%) of carriers could be missed by the current Israeli screening program. In total, 1:40 (2.5%) of carrier couples were identified by the ‘MyScreen’ panel, compared with 1:144 (0.7%) found by the ethnicity‐based screening. Surprisingly, 90 individuals (10.5%) were carriers of variants “unexpected” for their reported origin, and 16 variants were previously unreported in Jewish patients. Our results support the advantages of variant‐based comprehensive carrier screening for detection of carriers and at‐risk couples in a diverse population with many founder disease‐causing variants.

Community data-driven approach to identify pathogenic founder variants for pan-ethnic carrier screening panels

“…The pipeline started with 3847 variants that had been previously classified as P/LP in the 3061 samples. Initial filtration for reported P/LP variants that were not in the Israeli panel [ 15 ] and with carrier frequency ≥ 1/200 in either the Ashkenazi Jewish or Muslim Arab ancestry groups resulted in 195 variants (Additional file 1 : Table S2). Additional filtration steps for potential variants that should be included in carrier screening resulted in 25 potential novel PFVs in the Ashkenazi Jewish group and 18 potential PFVs in the Muslim Arab group, i.e., in total, 43 potential PFVs were identified in these two groups (Fig.…”

“…To assess the sensitivity of our pipeline, i.e., our ability to detect all known tier 2 and tier 3 variants, we used a commonly applied Israeli mutation-based carrier screening panel as a reference set [ 15 ]. We identified tier 2 or 3 variants from the existing carrier screening panel by calculating their estimated carrier frequency using an independent dataset taken from the gnomAD Ashkenazi Jewish population dataset and selecting those with a carrier frequency > 1/200.…”

“…Variants reported as P/LP by Franklin community members or ClinVar submissions were selected and compared with variants in an existing carrier screening panel dedicated to the Israeli population that is commonly used [ 15 ], in order to find novel PFVs (i.e., pathogenic variants not present in the existing panels). Frequencies of the candidate PFVs were calculated for each of the Israeli subpopulations based on the data of the cohort’s 3061 samples.…”

“…Finally, we compared these variants with existing carrier screening panels that are currently used. Two types of comparisons were performed: (1) four commercial NGS-based carrier screening panels: two Ashkenazi Jewish carrier screening panels with 64 (Sema4, Stamford, CT, USA) [ 17 ], and 48 genes (Inheritest, Labcorp, Burlington, NC, USA) [ 18 ], and two pan-ethnic carrier screening panels with 502 (Sema4 Elements, Sema4) [ 19 ], and 302 genes (Invitae, San Francisco, Ca, USA) [ 20 ]; and (2) genotype-based panel which was developed specifically for the Israeli population [ 15 ].…”

Are We Ready for Whole Population Genomic Sequencing of Asymptomatic Newborns?

“…Pilots in other screening contexts, such as reproductive carrier screening, that have used a genomic intervention as a first-line test have been very successful in indicating to a family that they might wish to consider a second-line intervention with a high degree of efficacy at a relatively low cost. 15,22 Which Conditions Should We Screen for?…”