Interpretation service for MODY gene variants of uncertain significance

Approximately 60-65% of mutations identified in MODY genes are novel (Colclough et al 2013 Hum Mutat 34, 669-685; Osbak et al 2009 Hum Mutat 30, 1512-1526; Chen et al 2010 Chin Med J (Engl) 123, 3326-3333), and variants of uncertain clinical significance are a common finding when sequencing MODY genes.  We offer an interpretation service for variants in the GCK, HNF1A, HNF4A and HNF1B genes identified by other laboratories performing genetic testing for MODY.

Users of this service will receive a fully interpretative diagnostic report, which will include an interpretation of the pathogenicity and clinical significance of the variant, and any suggested further investigations for the patient and/or their relatives.  A summary of the investigations undertaken to determine the pathogenicity of the variant is also available.

Investigations undertaken include:

• Assessment of the prior probability for a mutation in that gene according to the patient phenotype
• Comprehensive searches of the Human Gene Mutation Database (HGMD) Professional, Locus-specific databases, dbSNP, Exome Sequencing Project, 1000 genomes, published literature and our registry of MODY patients.
• Nucleotide and amino acid conservation, in silico analysis using SIFT, PolyPhen2, Align GVGD and Grantham score, and splicing predictions using SpliceSiteFinder-like, MatEntScan, NNSPLICE, GeneSplicer and Human Splicing Finder.

Our CPA accredited laboratory participates in the annual European Molecular Genetics Quality Network (EMQN) external quality assessment scheme for MODY.