238-LB: Prevalence of GCK-MODY in 92,412 Exomes from an Unselected Clinical Population

Abstract

Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes attributed to a highly penetrant variant in one of several genes, including GCK. GCK-MODY rarely requires pharmacotherapy, however, the clinical management of pregnant mothers depends on whether the fetus inherited the GCK variant. The classic GCK-MODY phenotype is young (diagnosed before 25 years), lean (BMI < 25 mg/kg2), with stable, mild hyperglycemia (Hba1c 5.8-7.6%). We hypothesized that strict application of these guidelines has led to under-reporting of GCK-MODY (prevalence 1.1 per 1000). In a cohort of 92,412 individuals from the DiscovEHR study, we identified 252 heterozygous carriers of 88 rare GCK variants (minor allele frequency < 0.02%). None had an existing diagnosis of monogenic diabetes. The median BMI of GCK carriers was 35 mg/kg2, compared to 31 mg/kg2 for nondiabetic noncarriers and 38 mg/kg2 for noncarriers with type 2 diabetes (T2D). Excluding variants with no evidence of hyperglycemia in 50% of the carriers resulted in 70 variants in 213 individuals. GCK-MODY variant carriers had mean HbA1c, fasting blood glucose (FBG), and random glucose measurements that were greater than nondiabetic non-carriers but less than those with T2D. Kaplan-Meier analysis adjusted for left-truncation bias showed that the age at which 50% of GCK-MODY subjects diagnosed with impaired fasting glucose and diabetes is 35 and 55 years, respectively, compared to 60 and 65 years in non-carriers with T2D (p< 2e-16). Within-individual variability of lifetime FBG measurements of GCK-MODY carriers was less than noncarriers with T2D (GCK-MODY, 7.9 ± 2.0 mg/dL; T2D, 17.6 ± 0.03 mg/dl, p <1e-4). The odds ratios [95% confidence intervals] for diabetes in GCK-MODY carriers was 4.0 [3.1 - 5.2], p<0.0001. We estimate a GCK-MODY prevalence of 1 per 508 individuals and 1 per 59 individuals with gestational diabetes. GCK variant carriers in this study had a broader spectrum of clinical characteristics compared to the classic GCK phenotype. Disclosure U.L. Mirshahi: None. J.M. Goehringer: None. Y. Hu: None. A.H. Wardeh: None. J. Williams: None. C.B. Manney: None. J.C. Staples: Employee; Self; Regeneron Pharmaceuticals. J.B. Leader: None. A.R. Shuldiner: Employee; Self; Regeneron Pharmaceuticals. Stock/Shareholder; Self; Rhythm Pharmaceuticals, Inc. T.I. Pollin: Other Relationship; Self; Regeneron Genetics Center. D.J. Carey: None.