Composite Digenic Diabetes Linked to Heterozygous Variants of GCK and NEUROD1: A Case Report

Introduction: We wanted to establish the etiologic cause of diabetes in a female subject with mild hyperglycemia since childhood, that suddenly worsened in her late 40s. We retrieved the proband’s laboratory data from the age of 5 years. We assessed type 1 diabetes autoantibodies and performed genetic screening by clinical exome. Case Presentation: The proband showed stable hyperglycemia not requiring pharmacological therapy for 42 years. The proband’s fasting plasma glucose increased from 120 to 130 mg/dL (6.1–7.2 mmol/L) to 150–159 mg/dL (8.3–8.8 mmol/L) at the age of 47 years. Four type 1 diabetes autoantibodies resulted repeatedly negative. A spontaneous glucokinase pathogenic variant (c.645C>A, p. Tyr215Ter) and a NEUROD1 variant (c.616dupC, p.His206ProfsTer38) were identified in the proband. Her mother, who carries the NEUROD1 variant, was diagnosed with diabetes by OGTT (120' = 211 mg/dL) when 77 years old. NEUROD1, a low penetrance maturity onset diabetes of the young (MODY) gene, is known to regulate gene transcription of GCK and SLC2A2, encoding for GLUT2, a functional partner of GCK in glucose sensing of the β cell. Conclusions: We conclude that the low penetrance NEUROD1 variant is likely responsible of the peculiar trajectory of fasting glucose in a subject who presented with classical metabolic phenotype associated with glucokinase haploinsufficiency from childhood to adulthood.