Early-onset diabetes involving three consecutive generations had different clinical features from age-matched type 2 diabetes without a family history

Abstract Objective Early-onset, multigenerational diabetes is a heterogeneous disease, which is often simplistically classified as type 1 diabetes (T1D) or type 2 diabetes(T2D). However, its clinical and genetic characteristics have not been clearly elucidated. The aim of our study is to investigate the clinical features of early-onset diabetes involving three consecutive generations (eDia3) in a Chinese diabetes cohort. Methods Of 6,470 type 2 diabetic patients, 105 were identified as eDia3 (1.6%). After a case-control match on age, we compared the clinical characteristics of 89 eDia3 patients with 89 patients with early-onset type 2 diabetes without a family history of diabetes (eDia0). WES was carried out in 89 patients with eDia3. We primarily focused on 14 known maturity-onset diabetes of the young (MODY) genes. Variants were predicted by ten tools (SIFT, PolyPhen2_HDIV, PolyPhen2_HVAR, LRT, Mutation Assessor, Mutation Taster, FATHMM, GERP++, PhyloP and PhastCons). All suspected variants were then validated by Sanger sequencing and further investigated in the proband families. Results Compared to age-matched eDia0, eDia3 patients had a younger age at diagnosis (26.5 ± 5.8 vs. 29.4 ± 5.3 years, P = 0.001), lower body mass index (25.5 ± 3.9 vs. 27.4 ± 4.6 kg/m2, P = 0.003), lower systolic blood pressure (120 ± 15 vs. 128 ± 18 mmHg, P = 0.003), and better metabolic profiles (including glucose and lipids). Of the 89 eDia3 patients, 10 (11.2%) carried likely pathogenic variants in genes (KLF11, GCK, ABCC8, PAX4, BLK and HNF1A) of maturity-onset diabetes of the young (MODY). Conclusions eDia3 patients have unique clinical features. Known MODY genes were not common causes in these patients.