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 the HNF1A gene encoding hepatocyte
nuclear factor-1 alpha are the most common cause of
MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding hepatocyte nuclear factor-4 alpha are a rarer cause of
MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea
tablets is a feature of both HNF1A and HNF4A mutations. 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 an HNF1A or HNF4A gene 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.