Overburden of rare ALMS1 deleterious variants in Chinese early‐onset type 2 diabetes with severe insulin resistance

Abstract Aims Alström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the ALMS1 gene have been identified as the causative agents of AS. This study aimed to explore the relationship between rare ALMS1 variants and clinical features in Chinese patients with early‐onset type 2 diabetes (age at diagnosis ≤40 years; EOD). Materials and Methods ALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre‐diabetes and fasting IR. In‐silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants. Results Sixty‐two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C‐peptide, postprandial C‐peptide, and HOMA2‐IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin‐resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre‐diabetes with fasting IR. Conclusions ALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function.