Genetic Carrier Burden in Neonatal Screening Genes: Evidence of Elevated Pathogenic Variant Frequency in the Lebanese population

Newborn screening programs (NSPs) are public health initiatives that aim to detect specific genetic conditions in asymptomatic newborns early enough to allow timely interventions, and decrease disease-associated morbidity. Despite the existing criteria for selecting disorders to be included in NSP, establishing a standardized global program remains challenging due to genetic diversity across regions. To better tailor the Lebanese national NSP, exome sequencing (ES) of 969 Lebanese individuals was analyzed for a panel of 109 genes associated with NSPs worldwide. A total of 168 pathogenic/likely pathogenic variants were detected in 54 genes, including 41 involved in metabolic diseases and 8 in severe primary immunodeficiencies (PID). The CFTR gene was found to be the most mutated gene (4.38% carrier rate), with c.1210-11T > G, associated with congenital bilateral absence of vas deferens, being the most common variant. The subsequent most commonly mutated genes were CYP21A2 (3.5%) , G6PD (2.75%) , MCCC2 (1.86%) and PAH (1.80%). Both CFTR and CYP21A2 are not currently included in the Lebanese NSP. Besides, 1.33% of our cohort carry pathogenic variants in genes involved in severe PID. In conclusion, this is the first ES-based study in the Lebanese population for NSP genes. Our findings underscore the value of integrating local genetic data and ES-based approaches into NSPs, to better reduce the burden of genetic diseases and improve public health outcomes.