Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin‐requiring antibody‐negative type 1 diabetes.

Background: Mutations in causative genes for neonatal diabetes or maturity‐onset diabetes of the young have been identified in multiple patients with autoantibody‐negative type 1 diabetes (T1D). Objectives: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody‐negative insulin‐requiring T1D. Methods: Mutations in 30 genes were screened using next‐generation sequencing, and copy‐number alterations of 4 major causative genes were examined using multiplex‐ligation‐dependent probe amplification. We compared the clinical characteristics between mutation carriers and non‐carriers. Results: We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy‐number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non‐carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non‐carriers, except for a relatively normal body mass index (BMI) at diagnosis. Conclusions: This study demonstrated significant genetic overlap between autoantibody‐negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin‐requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non‐carrier group. Carriers of monogenic mutations show non‐specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non‐carriers. [ABSTRACT FROM AUTHOR]

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