Background: ABCC8 variants cause neonatal diabetes, maturity onset diabetes of the young (MODY), and hyperinsulinemic hypoglycemia because of activating or inactivating variants. In this study we used targeted exon sequencing to investigate genetic variants of ABCC8 and phenotypic features in Chinese patients with early onset diabetes (EOD).

Methods: A cross-sectional study of 543 Chinese patients with EOD was recruited and the exons of them were conducted targeted sequencing. The pathogenicity of ABCC8 variants was defined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline. The phenotypes of patients owing to ABCC8 variants (ABCC8-MODY) were characterized.

Results: Among the 543 participants, eight (1.5%) patients with ABCC8-MODY were identified. They harbored eight missense ABCC8 variants (p.R306C, p.E1326K, and p.R1379H, previously reported; p.R298C, p.F1176C, p.R1221W, p.K1358R, and p.I1404V) classified as likely pathogenic. Two family members with ABCC8-MODY were also confirmed. The average diagnosed age of the 10 patients was 26.8 ± 12.9 years. The majority of them had unsatisfactory glucose control, 80% of them had diabetic kidney disease, and neurological features were not observed.

Conclusion: Using targeted exon sequencing followed by pathogenicity analysis, we could be able to make genetic diagnoses for eight (1.5%) patients with ABCC8-MODY. The phenotype was variable with higher risk of diabetic microvascular complications. Genetic diagnosis is conducive for facilitating the personalized treatment of ABCC8-MODY.

背景: ABCC8基因激活或失活变异可导致新生儿糖尿病、青年起病的成年型糖尿病(MODY)和高胰岛素血症低血糖。本研究中，我们利用靶向外显子测序方法在中国早发糖尿病(EOD)患者中检测ABCC8基因变异，分析ABCC8基因变异的临床特征。 方法: 我们纳入了543例中国EOD患者，详细收集临床资料，采用外显子靶向测序技术对ABCC8基因进行检测。根据“美国医学遗传学和基因组学会和分子病理学协会指南”分析ABCC8基因变异的致病性，并分析ABCC8基因变异(ABCC8-MODY)导致糖尿病患者的临床特征。 结果: 在543例患者中，遗传学确诊ABCC8-MODY患者8例(1.5%)。他们分别携带8个ABCC8基因错义突变(p.R306C、p.E1326K、 p.R1379H、p.R298C、p.F1176C、p.R1221W、p.K1358R、p.I1404V)，且均为可能致病性变异。同时发现2例家族成员为ABCC8-MODY。以上10例患者平均诊断年龄为26.8±12.9岁。大部分患者的血糖控制并不理想，80%患者有糖尿病肾病，未观察到神经肌肉合并症。 结论: 利用靶向外显子测序结合致病性分析，遗传学确诊8例(1.5%) ABCC8-MODY患者。此类患者的临床表型多样，糖尿病微血管并发症的发生风险较高。采用遗传学诊断有利于ABCC8-MODY的个体化治疗。.

Keywords: ABCC8; ABCC8基因; MODY; diabetic kidney disease; early onset diabetes; 早发糖尿病; 糖尿病肾病.