Abstract
CONTEXT: Monogenic diabetes testing in children currently targets maturity onset diabetes in the young (MODY) or recognized genetic syndromes. OBJECTIVE: We aim to determine whether genetic testing for monogenic diabetes should be performed for all children with diabetes and at least one non-autoimmune extra-pancreatic feature (syndromic diabetes). METHODS: We recruited 183 children with diabetes and at least one non-autoimmune extra-pancreatic feature (50% [n = 91] with self-reported consanguinity). We measured islet-autoantibodies and type 1 diabetes (T1D) genetic risk score (T1DGRS) and used targeted next-generation sequencing to analyze all known causes of monogenic diabetes. RESULTS: Of the children, 33% (61/183) had confirmed monogenic diabetes. Of these, 84% (51/61) had recessive etiologies with variants in WFS1 (46%), SLC19A2 (12%) and SLC29A3 (12%) being most common. Monogenic cases compared to non-monogenic had similar age of diagnosis (7.4 vs 6, P = .1) and body mass index z-score (-0.08 vs -0.41, P = .3) but had higher parental consanguinity (62% vs 19%, P = .01) and features in multiple organ systems (53% vs 28%, P = .01). Only 59% reported well-recognized features of their associated genetic syndrome. Children with low T1DGRS (<50th centile of T1D population) and negative/untested antibodies were more likely to have monogenic cause compared to positive antibodies or negative/untested antibodies and a high T1DGRS (≥ 50th centile) (48% vs 3% vs 7%, P < .0001). CONCLUSION: Children with diabetes and at least one non-autoimmune extra-pancreatic feature should be considered for monogenic diabetes testing. Measurement of islet-autoantibodies and T1DGRS help prioritize genetic testing.