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Strategic validation of variants of uncertain significance inECHS1genetic testing

生物 基因检测 计算生物学 遗传学 内科学 生物信息学 医学 计算机科学
作者
Yoshihito Kishita,Ayumu Sugiura,Takanori Onuki,Tomohiro Ebihara,Tetsuro Matsuhashi,Masaru Shimura,Takuya Fushimi,Noriko Ichino,Yoshie Nagatakidani,Hitomi Nishihata,Kazuhiro R. Nitta,Yukiko Yatsuka,Atsuko Imai‐Okazaki,Yibo Wu,Hitoshi Osaka,Akira Ohtake,Kei Murayama,Yasushi Okazaki
出处
期刊:Journal of Medical Genetics [BMJ]
卷期号:60 (10): 1006-1015 被引量:1
标识
DOI:10.1136/jmg-2022-109027
摘要

Background Enoyl-CoA hydratase short-chain 1 (ECHS1) is an enzyme involved in the metabolism of branched chain amino acids and fatty acids. Mutations in the ECHS1 gene lead to mitochondrial short-chain enoyl-CoA hydratase 1 deficiency, resulting in the accumulation of intermediates of valine. This is one of the most common causative genes in mitochondrial diseases. While genetic analysis studies have diagnosed numerous cases with ECHS1 variants, the increasing number of variants of uncertain significance (VUS) in genetic diagnosis is a major problem. Methods Here, we constructed an assay system to verify VUS function for ECHS1 gene. A high-throughput assay using ECHS1 knockout cells was performed to index these phenotypes by expressing cDNAs containing VUS. In parallel with the VUS validation system, a genetic analysis of samples from patients with mitochondrial disease was performed. The effect on gene expression in cases was verified by RNA-seq and proteome analysis. Results The functional validation of VUS identified novel variants causing loss of ECHS1 function. The VUS validation system also revealed the effect of the VUS in the compound heterozygous state and provided a new methodology for variant interpretation. Moreover, we performed multiomics analysis and identified a synonymous substitution p.P163= that results in splicing abnormality. The multiomics analysis complemented the diagnosis of some cases that could not be diagnosed by the VUS validation system. Conclusions In summary, this study uncovered new ECHS1 cases based on VUS validation and omics analysis; these analyses are applicable to the functional evaluation of other genes associated with mitochondrial disease.
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