Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes

摘要

Monogenic diabetes due to mutations in the transcription factor genes HNF1A and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, hepatocyte nuclear factor 1A (HNF1A) and hepatocyte nuclear factor 4A (HNF4A). The proband was diagnosed with diabetes at 7 years of age and treated with insulin for 4 years. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 years of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over two years. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 years of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 years, respectively.Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.