Diabetes research and clinical practice · 2026
Genetics and clinical landscape of pediatric monogenic diabetes in consanguineous cohort: high diagnostic yield and recessive burden.
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Shaikh Adnan Al, Alsagheir Afaf, Bahha Abdullah Talal, Alharthi Mohammed, Bunyan Abdulhameed Al, Alyahyawi Naseem Yahya, Harbi Tahani Al, Al Hakim Sarah Y, Mohammed Moneera, Noaim Khalid Al, Majrashi Nada, Almutair Angham, Al-Hamed Mohamed H
Аннотация
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.
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.