Table_3_Precision therapy for three Chinese families with maturity-onset diabetes of the young (MODY12).docx

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.

青少年起病的成年型糖尿病（Maturity-onset diabetes of the young, MODY）是一种罕见的单基因糖尿病。然而，MODY常被漏诊或误诊。
本研究旨在探究糖尿病的致病基因，并为3个家系的糖尿病患者提供精准治疗方案。本研究纳入3个疑似MODY的家系，采用全外显子组测序（Whole exome sequencing, WES）对其生殖系突变进行筛查，并在其他家系成员及无亲缘关系的健康对照中验证候选致病变异。
研究结果显示，分别在A、B、C三个家系中发现ABCC8基因（NM_001287174）上的3个杂合错义突变：c.1555 C>T (p.R519C)、c.3706 A>G (p.I1236V) 及c.2885 C>T (p.S962L)。所有突变位点均与糖尿病表型共分离，经生物信息学预测均具有致病性，且在无亲缘关系的健康对照中未被检出。
2例先证者（发病年龄分别为8岁和12岁）对格列美脲敏感，但初始剂量2 mg/日引发了酮症酸中毒；当格列美脲剂量增至4 mg/日时，血糖得以平稳控制。1例25岁的成年患者采用4 mg/日的格列美脲剂量后，血糖同样得到有效控制。此外，所有患者均对利拉鲁肽敏感，其控糖效果更佳。
本研究数据表明，ABCC8基因是这3个糖尿病家系的致病基因。2 mg/日的格列美脲无法有效控制携带ABCC8突变的儿童患者的血糖，但4 mg/日的格列美脲可在成人及儿童患者中均实现有效控糖。此外，利拉鲁肽对携带ABCC8突变的成人及儿童患者均具有良好的控糖效果。