Pathogenic variant-based preconception carrier screening in the Israeli Jewish population.

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.

Accelerated replicative senescence of ataxia-telangiectasia skin fibroblasts is retained at physiologic oxygen levels, with unique and common transcriptional patterns.

The genetic disorder, ataxia-telangiectasia (A-T), is caused by loss of the homeostatic protein kinase, ATM, and combines genome instability, tissue degeneration, cancer predisposition, and premature aging. Primary fibroblasts from A-T patients exhibit premature senescence when grown at ambient oxygen concentration (21%). Here, we show that reducing oxygen concentration to a physiological level range (3%) dramatically extends the proliferative lifespan of human A-T skin fibroblasts. However, they still undergo senescence earlier than control cells grown under the same conditions and exhibit high genome instability. Comparative RNA-seq analysis of A-T and control fibroblasts cultured at 3% oxygen followed by cluster analysis of differentially expressed genes and functional enrichment analysis, revealed distinct transcriptional dynamics in A-T fibroblasts senescing in physiological oxygen concentration. While some transcriptional patterns were similar to those observed during replicative senescence of control cells, others were unique to the senescing A-T cells. We observed in them a robust activation of interferon-stimulated genes, with undetected expression the interferon genes themselves. This finding suggests an activation of a non-canonical cGAS-STING-mediated pathway, which presumably responds to cytosolic DNA emanating from extranuclear micronuclei detected in these cells. Senescing A-T fibroblasts also exhibited a marked, intriguely complex alteration in the expression of genes associated with extracellular matrix (ECM) remodeling. Notably, many of the induced ECM genes encode senescence-associated secretory phenotype (SASP) factors known for their paracrine pro-fibrotic effects. Our data provide a molecular dimension to the segmental premature aging observed in A-T patients and its associated symptoms, which develop as the patients advance in age.