A high-fidelity long-read sequencing-based approach enables accurate and effective genetic diagnosis of spinal muscular atrophy

脊髓性肌萎缩 遗传诊断 遗传学 生物 医学 忠诚 计算生物学 生物信息学 计算机科学 病理 基因 疾病 电信
作者
Jin-li Bai,Yue Qu,Wen‐Chen Huang,Wanli Meng,Jiahan Zhan,Hong Wang,Wen-Qi Hou,Yuwei Jin,Aiping Mao,Fang Song
出处
期刊:Clinica Chimica Acta [Elsevier]
卷期号:553: 117743-117743 被引量:2
标识
DOI:10.1016/j.cca.2023.117743
摘要

We aimed to develop a high-fidelity long-read sequencing (LRS)-based approach to detect SMN gene variants in one step. It is challenging for conventional step-wise methods to simultaneously detect all kinds of variations between homologous SMN1 and SMN2. In this study, LRS was developed to analyze copy numbers (CNs), full sequences, and structure of SMN1 and SMN2. The results were compared with those from the step-wise methods in 202 samples from 67 families. LRS achieved 100% (202/202) and 99.5% (201/202) accuracy for SMN1 and SMN2 CNs, respectively. It corrected SMN1 CNs from MLPA, which was caused by SNVs/indels that located in probe-binding region. LRS identified 23 SNVs/indels distributing throughout SMN1, including c.22dup and c.884A > T in trans-configuration, and a de novo variant c.41_42delinsC for the first time. LRS also identified a SMN2 variant c.346A > G. Moreover, it successfully determined Alu-mediated 8978-bp deletion encompassing exon 2a-5 and 1415-bp deletion disrupting exon 1, and the exact breakpoints of large deletions. Through haplotype-based pedigree trio analysis, LRS identified SMN1 2 + 0 carriers, and determined the distribution of SMN1 and SMN2 on two chromosomes. LRS represents a more comprehensive and accurate diagnosis approach that is beneficial to early treatment and effective management of SMA.
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