Clinical and Genetic Characteristics of Patients with Early-Onset Diabetes Involving at Least Two Consecutive Generations: Whole-Exome Sequencing in Probands from 25 Pedigrees.

Background: The molecular mechanisms of early-onset multigenerational diabetes remain unknown. This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations.

Methods: From 1296 inpatients with diabetes, we selected individuals who were ≤ 30 years of age and who were clinically suspected of having familial monogenic diabetes. Clinical data were collected from the probands and their family members. Whole-exome sequencing (WES) was used to identify possible causal variants for diabetes. Candidate pathogenic variants were verified by Sanger sequencing, assessed for cosegregation in family members, and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Moreover, missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2. RNAfold was used to predict RNA structural alterations for synonymous variants.

Results: Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled. Pathogenic/likely pathogenic variants (p.Gly292fs in HNF1A, p.Gly245Argfs*22 in PDX1, p.Asp329His in KCNJ11, p.Leu734Phe and p.Val606Gly in WFS1) were detected in four patients, who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results. The variants of uncertain significance (ABCC8 c.3039 G > A (p.Ser1013 = Ser), MAPK8IP1 p.Gln144_Gly145insSerGln, and TBC1D4 p.Arg1249Trp) were identified in three probands.

Conclusion: Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants. Genetic testing in this population enables precision diagnosis, informs individualized treatment, and facilitates genetic counseling.