A new screening strategy and whole-exome sequencing for the early diagnosis of maturity-onset diabetes of the young.

Abstract

This study aimed to establish a systematic screening strategy to select candidates for genetic testing among patients with maturity-onset diabetes of the young (MODY) and to accomplish early diagnosis of MODY. We enrolled 1478 sporadic patients from the outpatient department of endocrinology. Out of the1478 patients, 1279 participants were successfully screened according to the "AACM" strategy, which includes the age of onset, autoantibody to islet antigen, C-peptide and metabolic syndrome. Another six probands and their families who fulfilled the common clinical criteria for MODY were also examined for causative gene mutations. Whole-exome sequencing (WES) was performed to examine the mutations. A total of 24 out of 1279 sporadic patients with newly diagnosed diabetes were eligible for genetic testing. Mutations were found in 4/24 participants in the cohort, as well as in 2/6 pedigrees. A likely pathogenic alteration, a likely benign alteration and three alterations with uncertain significance were identified with WES. Most of the mutant genes recognised in our trial were not the most common causative genes of MODY, and all of the mutations were specifically reported in Asian patients only, suggesting a unique genetic background of MODY in different ethnicities. In this systematic study of MODY in a new-onset diabetes cohort, MODY cases were incorrectly diagnosed as type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), suggesting that an observant clinician is necessary for early and correct MODY diagnosis. This systematic approach to screening is practical and specific enough to identify patients who are most appropriate for genetic testing.