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This study evaluated exome sequencing-based preconception carrier screening in 787 couples from the Mexican Jewish Community, an endogamous population with elevated risk for specific genetic disorders. The researchers identified 49 couples (6.2%) sharing autosomal recessive carrier status, with exome sequencing detecting 12 at-risk couples (24.4% of positive cases) that would have been missed by standard genetic panels. The analysis revealed 920 rare pathogenic variants including 146 previously unreported alleles, demonstrating the unique genetic profile of this population.
Why it matters
This research demonstrates that comprehensive exome sequencing significantly outperforms traditional panel-based carrier screening in endogamous populations, potentially preventing severe genetic diseases in children. The identification of population-specific variants supports the development of tailored screening programs for the Mexican Jewish Community and similar genetically isolated groups.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Introduction: Preconception 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. Objectives: To 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. Methods: From 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. Results: Shared 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. Conclusion: ES-based PCS improves detection of at-risk couples beyond conventional screening and supports its use in endogamous populations.