Precision therapy for three Chinese families with maturity-onset diabetes of the young (MODY12)

Abstract

Maturity-onset diabetes of the young (MODY) is rare monogenic diabetes. However, MODY is often undiagnosed or misdiagnosed. In this study, we aimed to investigate the pathogenic gene for diabetes and provide precise treatment for diabetes patients in three families. Three families with suspected MODY were enrolled and screened for germline mutations using Whole exome sequencing (WES). Candidate pathogenic variants were validated in other family members and non-related healthy controls. Three heterozygous missense mutations in the ABCC8 gene (NM_001287174), c.1555 C>T (p.R519C), c.3706 A>G (p.I1236V), and c.2885 C>T (p.S962L) were found in families A, B, and C, respectively. All mutation sites cosegregated with diabetes, were predicted to be harmful by bioinformatics and were not found in non-related healthy controls. Two probands (onset ages, 8 and 12 years) were sensitive to glimepiride. However, an insufficient dose (2 mg/day) led to ketoacidosis. When the dosage of glimepiride was increased to 4 mg/day, blood sugar remained under control. A dose of 4 mg glimepiride daily also effectively controlled blood sugar in an adult patient 25-year-old. In addition, all patients were sensitive to liraglutide, which could control blood sugar better. These data suggest that ABCC8 was the pathogenic gene in three families with diabetes. Glimepiride (2 mg/day) was not effective in controlling blood sugar in children with ABCC8 mutations, however, 4 mg/daily glimepiride was effective in both adults and children. Moreover, liraglutide was effective in controlling blood sugar in both adults and children with ABCC8 mutations.

Keywords: ABCC8; MODY12; mutation; precision therapy; whole exome sequencing.

Figure 1

Pedigree of the three families. Squares represent males, while circles represent females. The red border represents diabetes, the blackened box represents the proband. (A) proband A’s family pedigree; (B) proband B’s family pedigree; (C) proband C’s family pedigree. The genotypes of each variation of c.1555 C>T, c.3706 A>G, and c.2885 C>T in the ABCC8 gene are shown in families (A–C), respectively.

Figure 2

The sequencing chromatogram. Arrows indicate the changed position of the mutation in ABCC8 gene. Family A: (A) (wild type) and (B) (mutant type); Family B: (C) (wild type) and (D) (mutant type); Family C: (E) (wild type) and (F) (mutant type).