Children With Diabetes and At Least One Non-Autoimmune Feature Should Be Considered for Monogenic Diabetes Testing.

Abstract

Monogenic diabetes testing in children currently targets maturity onset diabetes in the young (MODY) or recognized genetic syndromes. 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). 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. 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). 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.