Exome-based Preconception Carrier Screening for the Mexican Jewish Community; Yields and Implications

Abstract

IntroductionPreconception carrier screening (PCS) reduces monogenic disease incidence, exemplified by a 90% decline in Tay-Sachs among Ashkenazi populations. The Mexican Jewish Community (MJC), an endogamous population, may have increased prevalence of population-specific genetic disorders. The added value of exome sequencing (ES) over standard panels remains unclear. ObjectivesTo identify pathogenic/likely pathogenic (P/LP) variants in autosomal recessive (AR), X-linked (XL), and mitochondrial genes, evaluate secondary findings (SF), and define population-specific allele frequencies in the MJC. MethodsFrom 2020-2025, 787 couples (1,574 individuals) underwent ES following counseling and consent. Genetic data was analyzed including SNVs, CNVs, and mitochondrial DNA. Reporting was limited to P/LP variants and SF. ResultsShared AR carrier status was identified in 49 couples (6.2%): 18.4% associated with severe, 16.3% moderate, and 65.3% with mild conditions. In 71.4% of couples, both partners carried the same variant, consistent with endogamy within the cohort. Maternal findings were identified in 10 women (1.27%). Clinically actionable SF were found in 2.85% of individuals. ES identified 12 at-risk couples (24.4%), undetected by standard panels. Individual genomic profiling revealed 920 rare P/LP variants, including 146 novel alleles, underscoring the distinct genetic architecture of the MJC. ConclusionES-based PCS improves detection of at-risk couples beyond conventional screening and supports its use in endogamous populations.