Monogenic Diabetes (MODY and Neonatal Diabetes Mellitus) in Saudi Arabia: Genetic Spectrum, Clinical Phenotype, and Diagnostic Gap—A Systematic Review and Meta-Analysis

Background and Aims: Monogenic diabetes — encompassing maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM) — accounts for an estimated 1–5% of all diabetes diagnoses worldwide, yet remains chronically misclassified as type 1 or type 2 diabetes. Correct molecular assignment carries direct therapeutic implications: HNF1A/HNF4A-MODY is sulfonylurea-sensitive, GCK-MODY requires no pharmacotherapy, and KCNJ11/ABCC8-NDM can be transitioned from insulin to oral sulfonylureas with dramatic glycaemic and neurodevelopmental improvement. Saudi Arabia’s consanguinity rate of approximately 56%, combined with multiple disease-causing founder mutations, places it among the world’s highest-burden countries for monogenic diabetes. No previous systematic review has synthesised the Saudi evidence base. We conducted this review to quantify pooled diagnostic yield, characterise the genetic spectrum, and describe clinical outcomes in Saudi patients with molecularly confirmed monogenic diabetes. Methods: We conducted a PRISMA 2020-compliant systematic review and meta-analysis. Searches of PubMed/MEDLINE, Embase, Scopus, Web of Science Core Collection, Cochrane CENTRAL, and the Saudi Digital Library were executed in April 2026 from database inception, with no language restriction. Additional sources included the Saudi Human Genome Program portal, the CAGS-CTGA database, and grey literature. Two reviewers independently screened records in Rayyan (blinded mode) and extracted data using a pre-piloted template. Risk of bias was assessed with JBI Critical Appraisal Checklists, the Newcastle–Ottawa Scale, and QUADAS-2 where applicable. Proportions were pooled using random-effects meta-analysis with Freeman–Tukey double arcsine transformation. Certainty of evidence was graded using the GRADE framework. Results: Seventeen studies comprising 512 patients met inclusion criteria. The pooled diagnostic yield of genetic testing was 68.4% (95% CI 55.1–80.2%; I² = 61%; 95% prediction interval 32.7–94.1%). Yields were highest with whole-exome sequencing (WES, 74.2%; 95% CI 62.8–84.1%; I²= 38%) and NDM-focused cohorts (79.4%; 95% CI 68.3–88.7%; I² = 29%). EIF2AK3 (Wolcott–Rallison syndrome) was the dominant gene, representing 28.3% of all molecularly confirmed diagnoses; KCNJ11 and ABCC8 together accounted for 31.7% of confirmed NDM. Regional NDM incidence was estimated at 1 per 22,400 live births (95% CI: 1/18,100–1/28,700) — approximately 4.5-fold the global estimate. Misdiagnosis as type 1 or type 2 diabetes preceded molecular diagnosis in 61.3% (95% CI 51.8–70.4%) of patients. The median diagnostic delay was 14.3 months (IQR 6.4–28.7). Sulfonylurea transition was attempted in 89 patients with KCNJ11/ABCC8-NDM; 84.3% (95% CI 71.2–94.3%) achieved sustained insulin discontinuation. Certainty of evidence was low to very low owing to risk of bias and imprecision. Conclusions: Saudi Arabia carries a disproportionate and substantially undercharacterised burden of monogenic diabetes, particularly NDM caused by EIF2AK3, KCNJ11, and ABCC8 mutations. Diagnostic yield is high in appropriately referred patients and treatment-modifying mutations are common. A national monogenic diabetes registry, standardised clinical suspicion algorithms, and funded first-tier WES for all Saudi children presenting with diabetes under two years of age represent evidence-grounded health-system priorities.