Mutations in the Genes Encoding the Transcription Factors Hepatocyte Nuclear Factor 1 Alpha and 4 Alpha in Maturity-Onset Diabetes of the Young and Hyperinsulinemic Hypoglycemia

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Maturity-onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young-onset (typically <25 years), noninsulin-dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in theHNF1Agene encoding hepatocyte nuclear factor-1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenicHNF1Amutations totals 414 in 1,247 families. Mutations in theHNF4Agene encoding hepatocyte nuclear factor-4 alpha are a rarer cause of MODYwith 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of bothHNF1AandHNF4Amutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in ˜50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of anHNF1AorHNF4Agene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost-effective gene analysis for all patients with young onset diabetes.

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