Exome Sequencing and Genetic Testing for MODY
Open Access
- 25 May 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (5), e38050
- https://doi.org/10.1371/journal.pone.0038050
Abstract
Genetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic potential when standard Sanger sequencing-based diagnostics is inconclusive. The aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results. We performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism. On average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0–4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes. Our results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized.This publication has 49 references indexed in Scilit:
- Clinical and Metabolic Features of Adult-Onset Diabetes Caused by ABCC8 MutationsDiabetes Care, 2012
- Heterozygous ABCC8 mutations are a cause of MODYDiabetologia, 2011
- Role of molecular genetics in transforming diagnosis of diabetes mellitusExpert Review of Molecular Diagnostics, 2011
- Whole-Exome-Sequencing-Based Discovery of Human FADD DeficiencyAmerican Journal of Human Genetics, 2010
- The diagnosis and management of monogenic diabetes in children and adolescentsPediatric Diabetes, 2009
- Non-DNA binding, dominant-negative, human PPARγ mutations cause lipodystrophic insulin resistanceCell Metabolism, 2006
- Activating Mutations in theABCC8Gene in Neonatal Diabetes MellitusThe New England Journal of Medicine, 2006
- Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidismNature Genetics, 2006
- Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertensionNature, 1999
- Familial Hyperglycemia Due to Mutations in Glucokinase -- Definition of a Subtype of Diabetes MellitusThe New England Journal of Medicine, 1993