HLA-guided identification of monogenic diabetes in antibody-negative type 1 diabetes: frequency and characteristics

Antibody-negative type 1 diabetes (T1D) is a provisional diagnosis with unclear etiology. This study aimed to determine the prevalence and phenotypic characteristics of monogenic diabetes within a large antibody-negative T1D cohort.

A total of 482 antibody-negative T1D patients were included from a clinically diagnosed T1D cohort. Targeted sequencing using a custom gene panel covering 36 genes and the mitochondrial 3243 A > G mutation was performed. Demographic, metabolic, and human leukocyte antigen (HLA) data were analyzed. Beta-cell function was assessed in patients with monogenic diabetes amenable to precision treatment.

Among 482 antibody-negative T1D patients, 2.5% (12/482) had maturity-onset diabetes of the young (MODY) and 1.7% (8/482) had mitochondrial diabetes. The prevalence of MODY increased to 11.1% (6/54) among childhood-onset patients with a single susceptible HLA haplotype, while mitochondrial diabetes reached 6.2% (7/113) in adult-onset patients lacking HLA-susceptible haplotypes. Other characteristics, including gender, age at diagnosis, hemoglobin A1c, 2-hour postprandial C-peptide (2hCP), and family history of diabetes, showed no significant differences. Compared with the "truly" antibody-negative T1D group, MODY patients had an earlier onset, whereas mitochondrial diabetes patients had later onset, higher 2hCP, and fewer HLA-susceptible haplotypes (all P < 0.05). Of eight recalled monogenic diabetes patients, 62.5% (5/8) retained random C-peptide > 100 pmol/L after a median 15.7 years.

In antibody-negative T1D, MODY and mitochondrial diabetes accounted for 2.5% and 1.7%, respectively. HLA genotype was the key distinguishing factor. Persistent C-peptide secretion in monogenic diabetes supports the need for genetic screening in antibody-negative T1D patients.