An Effective and Universal Long-Read Sequencing-Based Approach for SMN1 2 + 0 Carrier Screening through Family Trio Analysis

SMN1型 单倍型 形状记忆合金* 遗传学 先证者 等位基因 载波测试 生物 脊髓性肌萎缩 基因 算法 计算机科学 产前诊断 突变 怀孕 胎儿
作者
Shuyuan Li,Xu Han,Liang Zhang,Yan Xu,Chunxin Chang,Li Gao,Jiahan Zhan,Renyi Hua,Aiping Mao,Yanlin Wang
出处
期刊:Clinical Chemistry [American Association for Clinical Chemistry]
卷期号:69 (11): 1295-1306 被引量:1
标识
DOI:10.1093/clinchem/hvad152
摘要

Population-wide carrier screening for spinal muscular atrophy (SMA) is recommended by professional organizations to facilitate informed reproductive options. However, genetic screening for SMN1 2 + 0 carriers, accounting for 3%-8% of all SMA carriers, has been challenging due to the large gene size and long distance between the 2 SMN genes.Here we repurposed a previously developed long-read sequencing-based approach, termed comprehensive analysis of SMA (CASMA), to identify SMN1 2 + 0 carriers through haplotype analysis in family trios (CASMA-trio). Bioinformatics pipelines were developed for accurate haplotype analysis and SMN1 2 + 0 deduction. Seventy-nine subjects from 24 families composed of, at the minimum, 3 were enrolled, and CASMA-trio was employed to determine whether an index subject with 2 SMN1 copies was a 2 + 0 carrier in these families. For the proof-of-principle, SMN2 2 + 0 was also analyzed.Among the 16 subjects with 2 SMN1 copies, CASMA-trio identified 5 subjects from 4 families as SMN1 2 + 0 carriers, which was consistent with pedigree analysis involving an affected proband. CASMA-trio also identified SMN2 2 + 0 in six out of 43 subjects with 2 SMN2 copies. Additionally, CASMA-trio successfully determined the distribution pattern of SMN1 and SMN2 genes on 2 alleles in all 79 subjects.CASMA-trio represents an effective and universal approach for SMN1 2 + 0 carriers screening, as it does not reply on the presence of an affected proband, certain single-nucleotide polymorphisms, ethnicity-specific haplotypes, or complicated single-nucleotide polymorphism analysis across 3 generations. Incorporating CASMA-trio into existing SMA carrier screening programs will greatly reduce residual risk ratio.
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