Supplementary Material for: 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 proband's laboratory data from age of 5 years. We assessed type 1 diabetes autoantibodies and performed genetic screening by clinical exome.
Case presentation. Proband showed stable hyperglycemia not requiring pharmacological therapy for 42 years. Proband's fasting plasma glucose increased from 120-130 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 NEUROD1variant (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 trascription of GCK and SLC2A2, encoding for GLUT2, a functional partner of GCK in glucose sensing of the  cell.
Conclusions. We conclude that the low penetrance NEUROD1 variant is 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.