Hepatocyte nuclear factor (HNF)1A and HNF4A substitution occurring simultaneously in a family with maturity‐onset diabetes of the young

Introduction Maturity‐onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by an early age at onset, autosomal dominant inheritance and a primary defect in the function of the B‐cells of the pancreas. We report a family with two members carrying a substitution in both the hepatocyte nuclear factor (HNF)1A and HNF4A gene simultaneously. Case report A 39‐year‐old man was referred because of mild diabetic retinopathy. Because of a dominant presentation of diabetes in his family, genetic testing was performed. Sequence analysis of the genes involved in MODY‐1–3 revealed the presence of an amino acid substitution in the HNF1A as well as the HNF4A gene. Both substitutions were also detected in his mother. The HNF1A substitution has been described previously as pathogenic, whereas the HNF4A substitution had not been found previously. The HNF4A substitution was located in a conserved region of the protein and, additionally, the proband and his mother had high birthweights and low triglyceride levels, both of which are associated with pathogenic HNF4A substitutions. Conclusions To our knowledge this is the first reported family carrying both a substitution of HNF1A and HNF4A gene simultaneously. The exact contribution of each substitution to the phenotype of our subjects remains to be further elucidated, however, given the high birthweights and the low triglyceride levels in those with both substitutions, it is reasonable that the HNF4A substitution is pathogenic.