Genomic Clinical Variant Expert Curation Panel for Monogenic Diabetes: A Gateway to Precision Medicine in Diabetes Mellitus

PROJECT SUMMARY Diabetes mellitus, a heterogeneous group of diseases characterized by hyperglycemia, affects over 37 million individuals in the United States and 422 million worldwide and is a leading cause of cardiovascular disease, blindness, end-stage renal disease and death. Maternal diabetes is also associated with risk for poor pregnancy outcomes. Highly penetrant genetic forms of diabetes including maturity onset diabetes of the young (MODY), neonatal diabetes, and syndromes that comprise both diabetes and developmental and intellectual disabilities account for at least 1% of diabetes, or over 340,000 cases nationwide. Distinguishing these genetic forms of diabetes from type 1 (T1D) and type 2 diabetes (T2D) demonstrably improves glucose control and quality of life by enabling replacement of invasive insulin treatment and/or ineffective oral treatment with less invasive and more efficacious etiology-based oral or dietary treatment for the patients and their affected family members. In some cases, the individualized treatment can ameliorate neurological dysfunction. However, recent studies show that most cases are misdiagnosed. There are several barriers to improving the diagnosis rate, including lack of awareness, clinical overlap with other diabetes types, expense of testing, genetic heterogeneity and predominance of rare variants. With the advent of next generation sequencing techniques, testing is becoming increasingly feasible and cost-effective, but for its true potential to be realized, a systematic process for the pooling, annotation and curation of variants is needed. Thus, we have established an international ClinGen Monogenic Diabetes Expert Panel (MDEP) with both Variant Curation (VCEP) and Gene Curation (GCEP) components consisting over 60 members and have developed gene- specific rules for classifying MODY variants, curated hundreds of variants for deposit into ClinVar, and curated the relationship with diabetes of all genes asserted as MODY genes. We now propose to move another step toward our goal of true precision medicine for diabetes mellitus through comprehensive curation of the relationship of diabetes and congenital hyperinsulinemic hypoglycemia with 70+ genes which have been proposed as monogenic diabetes genes and to develop and apply gene specific rules to the curation of variants in monogenic forms of autoimmune diabetes and insulin resistance/lipodystrophies, which have individualized treatment implications distinct from the MODYs, including the opportunity to prevent extra- pancreatic disease in multi-organ autoimmune forms and to treat the underlying leptin deficiency found in many lipodystrophies.