Genetics and clinical landscape of pediatric monogenic diabetes in consanguineous cohort: high diagnostic yield and recessive burden.
BACKGROUND Monogenic diabetes mellitus (MDM) comprises a heterogeneous group of rare disorders caused by single-gene defects. Data from highly consanguineous Middle Eastern populations remain scarce, which limits the application of precision medicine in these regions. OBJECTIVE To characterize the genetic spectrum, clinical features, and inheritance patterns of MDM within a large Saudi Arabian cohort. METHODS Exome sequencing (ES) and clinical analysis were conducted for 135 Saudi patients from 86 unrelated families. Variants were classified according to ACMG guidelines. RESULTS The cohort (52.6% male) exhibited a high consanguinity rate of 81%. A molecular diagnosis (Pathogenic/likely pathogenic) was achieved in 73% of families, with autosomal recessive inheritance predominating. Variant of uncertain significance (VUS) accounted for 15% of families. Leading clinical subtypes included MODY (33.3%), syndromic diabetes (27.4%), and permanent neonatal diabetes (23.7%). The most frequently implicated genes were INSR (13%), EIF2AK3 (12%), INS (11%), and GCK (11%). Furthermore, seven novel variants were identified. CONCLUSION MDM in Saudi Arabia is characterized by a high burden of autosomal recessive forms, including neonatal and syndromic diabetes, reflecting population structure and consanguinity. These findings highlight the importance of early genetic testing to guide management and genetic counseling.