The Landscape of Genetic Variation and Disease Risk in Romania: A Single-Center Study of Autosomal Recessive Carrier Frequencies and Molecular Variants

Autosomal recessive (AR) disorders represent a significant public health challenge, as asymptomatic carriers are often unaware of their reproductive risks. This study provides the first comprehensive assessment of AR gene variant frequencies and their molecular landscape in a fertile Western Romanian population. Genetic results from 604 unrelated, unaffected Caucasian individuals of reproductive age, tested at a single genetic center between 2020 and 2024, were retrospectively analyzed. Next-generation sequencing (NGS) with a multi-gene panel targeting 300 AR-associated genes was used for molecular profiling. Variants were identified in 156 genes, with 75% of individuals carrying at least one AR variant (mean 1.77 variants/person). A subgroup with >3 pathogenic variants comprised 7.5%, posing a notable risk for future offspring. The most frequent variants were detected in <i>HFE</i> (1:5), <i>CFTR</i> (1:9), <i>BTD</i> (1:16), <i>GJB2</i> (1:17), and <i>CYP21A2</i> (1:19). Four variants (<i>HFE</i>, c.187C>G; <i>BTD</i>, c.1330G>C; <i>CFTR</i>, c.1210-34TG[11]T[5]; <i>GALT</i>, c.-119_-116del) were particularly prevalent, each exceeding 3% frequency. Considerable allelic heterogeneity was observed for distrinctive variants in <i>CFTR</i> (14), <i>PAH</i> (12), <i>USH2A</i> (12), and <i>ATP7B</i> (9). Several variants were linked to severe disorders, with <i>CFTR</i>, <i>GALT</i>, <i>ATP7B</i>, and <i>SMN1</i> identified as "red zone" genes associated with high morbidity and mortality. Low-frequency variants formed a "long tail" (83.9%), reflecting marked population heterogeneity and potential hidden disease risks. The study reveals high allelic diversity and a strong prevalence of AR variants in Western Romania. Variant-based gene classification supports population-level screening, highlighting the public health value of a national program to identify carriers and prevent severe inherited disorders.