Homozygous hypomorphic HNF1A alleles are a novel cause of young-onset diabetes and result in sulphonylurea sensitive diabetes

Introduction: Heterozygous loss-of-function mutations in HNF1A cause MODY and affected individuals can be treated with low-dose sulphonylureas. Homozygous MODY-causing mutations are unreported. Methods: We phenotyped a kindred with young-onset diabetes, undertaking molecular genetic testing, a mixed meal tolerance test, a sulphonylurea challenge and in vitro assays to assess variant protein function. Results: A homozygous HNF1A variant (p.A251T) was identified in three inuslin-treated family members diagnosed with diabetes <20 years-of-age. Homozygous variant carriers had low hsCRP levels (0.2-0.8 mg/L) and, those tested, demonstrated sulphonylurea sensitivity at low-dose, with complete transition off insulin. In silico modelling predicted a variant of unknown significance, however in vitro studies supported a modest reduction (79% of wildtype p<0.05) in transactivation potential in the absence of endogenous HNF1A . Conclusion: Homozygous hypomorphic HNF1A variants are a cause of HNF1A-MODY. We expand the allelic spectrum of variants causing diabetes in dominant genes.

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