Bioinformatic detection of copy number variation in HNF4A causing maturity onset diabetes of the young

Abstract

To the Editor: Maturity onset diabetes of the young (MODY) is currently under-recognized clinically, and may also be under-recognized by molecular genetic analysis. Genetic testing for MODY is presently accomplished primarily using next generation sequencing (NGS) techniques. However, these techniques are historically unable to detect copy number variations (CNVs), defined as large-scale deletions or duplications in genomic DNA. We report here on a largescale heterozygous CNV in HNF4A causing MODY in an individual who initially tested negative for mutations by DNA sequencing alone. The proband carrying this mutation was a Caucasian female, diagnosed with diabetes at age 16. She has a normal body mass index with negative diabetes-associated autoantibodies and a significant family history of diabetes. She was managed effectively with a sulphonylurea for several years, with improvement in HbA1c from 7.5% to 5.6% compared to multiple daily injections of insulin. Sulphonylurea therapy eventually became ineffective and insulin was re-initiated.