Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.
Institute of Genomics and Integrative Biology (IGIB), New Delhi, India.
Sci Rep. 2020 Oct 14;10(1):17299. doi: 10.1038/s41598-020-73475-5.
Classical homocystinuria is the most common cause of isolated homocystinuria. The variants of the CBS gene remain unidentified in Indian children with this disorder. Based on the hallmark clinical features, family history, and/or biochemical clues for classical homocystinuria, 16 children below the age of 18 years were evaluated by Sanger sequencing of the coding exons of CBS gene with flanking intronic regions. The common C677T variant of the MTHFR gene was also screened by restriction fragment length polymorphism. Fifteen children were clinically suspected of having classical homocystinuria and one asymptomatic child with positive family history. Only seven children had biochemical features of classical homocystinuria. Sanger sequencing of the CBS gene confirmed 15 different pathogenic or likely pathogenic variants in 14 cases. Of these, seven variants were novel (three frameshift deletions, two nonsense, one missense, one splice site variant) and were predicted to be deleterious by Mutation Taster software. Seven cases were homozygous, another six were compound heterozygous, and one case was single heterozygous in the study. None of the three most frequent mutations reported worldwide viz., I278T, G307S, and IVS 11-2A>C were found in our cohort. No variants were detected in the exons 2, 8, 12, and 14 as compared to reported literature. Eleven out of 15 variants were associated with the conserved catalytic domain of the CBS polypeptide. The MTHFR polymorphism C677T was observed in heterozygous state in six cases. Our study reports the detailed genotype and seven novel variants in the CBS gene, causing classical homocystinuria in Indian children. The genetic analysis will help to offer accurate genetic counseling, prenatal diagnosis, and development of mutation-based novel therapeutic strategies.
经典同型胱氨酸尿症是孤立性同型胱氨酸尿症最常见的原因。在患有这种疾病的印度儿童中，CBS 基因的变体仍未被识别。根据经典同型胱氨酸尿症的标志性临床特征、家族史和/或生化线索，对 16 名 18 岁以下的儿童进行 CBS 基因编码外显子的 Sanger 测序，并进行侧翼内含子区域分析。还通过限制性片段长度多态性筛查 MTHFR 基因的常见 C677T 变体。15 名儿童临床疑似患有经典同型胱氨酸尿症，1 名无症状儿童有阳性家族史。只有 7 名儿童具有经典同型胱氨酸尿症的生化特征。CBS 基因的 Sanger 测序在 14 例中证实了 15 种不同的致病性或可能致病性变体。其中，7 种变体是新的（3 种移码缺失、2 种无义、1 种错义、1 种剪接位点变体），并且 Mutation Taster 软件预测这些变体具有有害性。7 例为纯合子，另 6 例为复合杂合子，1 例为研究中的单杂合子。在我们的队列中未发现全世界报道的 3 种最常见的突变，即 I278T、G307S 和 IVS 11-2A>C。与报道的文献相比，未在第 2、8、12 和 14 外显子中检测到变体。15 种变体中的 11 种与 CBS 多肽的保守催化结构域相关。CBS 基因中的 6 种变体观察到 MTHFR 多态性 C677T 为杂合状态。本研究报告了印度儿童中导致经典同型胱氨酸尿症的 CBS 基因的详细基因型和 7 种新变体。遗传分析将有助于提供准确的遗传咨询、产前诊断和基于突变的新型治疗策略的开发。
