Identifying Hepatic Nuclear Factor 1α Mutations in Children and Young Adults With a Clinical Diagnosis of Type 1 Diabetes

Abstract

OBJECTIVE—HNF-1α gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk of diabetes in other family members. We examined the prevalence of HNF-1α mutations in families with three generations of diabetes identified in a population-based study of childhood diabetes, representing a subpopulation in which misclassification was likely. RESEARCH DESIGN AND METHODS—In a study population of 1,470 families, 36 families (2.4%) with three affected generations were identified. In the 18 families in whom DNA samples were available, islet autoantibody testing, HLA class II genotyping, and HNF-1α sequencing were performed. RESULTS—At least one islet autoantibody was found in 13 of 14 probands, and diabetes-associated HLA class II haplotypes were found in 17 of 18. One proband, who had no islet autoantibodies and was homozygous for the protective HLA haplotype DRB1*02-DQB1*0602, had a novel HNF-1α heterozygous nonsense mutation (R54X). This mutation cosegregated with diabetes in the family. The proband, his brother, mother, and maternal grandmother were diagnosed with type 1 diabetes aged 14–18 years and treated with insulin (0.39–0.74 units/kg) from diagnosis. The mother has since been successfully transferred to sulfonylurea treatment. CONCLUSIONS—Family history alone is of limited value in identification of individuals with HNF-1α mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1α gene to those with a family history of diabetes who also test negative for islet autoantibodies.