Gene-specific function prediction for non-synonymous mutations in monogenic diabetes genes

PLoS One. 2014 Aug 19;9(8):e104452. doi: 10.1371/journal.pone.0104452. eCollection 2014.


The rapid progress of genomic technologies has been providing new opportunities to address the need of maturity-onset diabetes of the young (MODY) molecular diagnosis. However, whether a new mutation causes MODY can be questionable. A number of in silico methods have been developed to predict functional effects of rare human mutations. The purpose of this study is to compare the performance of different bioinformatics methods in the functional prediction of nonsynonymous mutations in each MODY gene, and provides reference matrices to assist the molecular diagnosis of MODY. Our study showed that the prediction scores by different methods of the diabetes mutations were highly correlated, but were more complimentary than replacement to each other. The available in silico methods for the prediction of diabetes mutations had varied performances across different genes. Applying gene-specific thresholds defined by this study may be able to increase the performance of in silico prediction of disease-causing mutations.

MeSH terms

  • Adolescent
  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Cycle Proteins / genetics
  • Child
  • Computational Biology / methods
  • Computational Biology / statistics & numerical data*
  • Diabetes Mellitus, Type 2 / diagnosis*
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-beta / genetics
  • Hepatocyte Nuclear Factor 4 / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Lipase / genetics
  • Mutation, Missense*
  • Paired Box Transcription Factors / genetics
  • Potassium Channels, Inwardly Rectifying / genetics
  • Repressor Proteins / genetics
  • Sulfonylurea Receptors / genetics
  • Trans-Activators / genetics
  • Young Adult
  • src-Family Kinases / genetics


  • ABCC8 protein, human
  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • HNF1A protein, human
  • HNF1B protein, human
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 4
  • Homeodomain Proteins
  • KLF11 protein, human
  • Kir6.2 channel
  • NEUROD1 protein, human
  • PAX4 protein, human
  • Paired Box Transcription Factors
  • Potassium Channels, Inwardly Rectifying
  • Repressor Proteins
  • Sulfonylurea Receptors
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Hepatocyte Nuclear Factor 1-beta
  • BLK protein, human
  • src-Family Kinases
  • CEL protein, human
  • Lipase

Supplementary concepts

  • Mason-Type Diabetes
  • Maturity-Onset Diabetes of the Young, Type 2