2264-PUB: Progress in Curating Gene–Disease Relationships by the ClinGen Monogenic Diabetes Expert Panel

Abstract

Diagnosing and distinguishing monogenic diabetes, including some MODY (maturity-onset diabetes of the young), from type 1 or type 2 diabetes can have profound clinical implications: sulfonylureas vs. insulin or metformin for HNF1A- and HNF4A- diabetes, and no treatment for GCK-diabetes. Since 1996, the number of monogenic diabetes genes has expanded from three to 60 or more, with 14 called MODY genes; however newer evidence has called some of these gene associations into question. Monogenic diabetes is currently underdiagnosed, but the decreasing cost of sequencing and the ability to create multi-gene next-generation sequencing panels may increase access to testing and a proper diagnosis. For the testing to be useful, it is important that the genes chosen for these panels have appropriate evidence as causal genes. The NIH Clinical Genome Resource (ClinGen) Monogenic Diabetes Gene Curation Expert Panel was convened to bring together experts in clinical and laboratory aspects of monogenic diabetes and gene curation to publish curations for the ClinGen website based on evidence from clinical and molecular studies and population databases. To date, we have published evidence-based gene curation summaries for Gene-Disease Validity for HNF1A and HNF4A (both classified as Definitive for monogenic diabetes) and are in the process of curating and publishing curations for GCK (Definitive for monogenic diabetes), INS (Definitive for monogenic diabetes and permanent neonatal diabetes), HNF1B (Definitive for renal cysts and diabetes), and KLF11 (Disputed for monogenic diabetes due to limited evidence and high population frequencies of variants previously asserted as causative). Curation of additional genes is in progress. Accurate curations will inform appropriate testing panel content to reduce ambiguous results and assure variants identified are clinically relevant for informing the care of diabetes in patients and their families. Disclosure T.I. Pollin: None. M.A. Mayers: None. S.W. Greeley: None. K.A. Maloney: None. R.N. Naylor: None. R.E. Pakyz: None. K.A. Patel: None. M. Udler: None. H. Zhang: None. K. Colclough: None. C. Thaxton: None. Funding National Institutes of Health (U24HD093486)