SMN1型
脊髓性肌萎缩
形状记忆合金*
载波测试
遗传学
数字聚合酶链反应
生物
多重聚合酶链反应
一致性
基因
聚合酶链反应
神经肌肉疾病
生物信息学
医学
病理
产前诊断
胎儿
数学
组合数学
疾病
怀孕
作者
Christopher Tan,M Jody Westbrook,Rebecca Truty,Daniel J. Kvitek,Michael Kennemer,Thomas Winder,Perry B. Shieh
出处
期刊:Genetic Testing and Molecular Biomarkers
[Mary Ann Liebert]
日期:2020-10-01
卷期号:24 (10): 616-624
被引量:9
标识
DOI:10.1089/gtmb.2019.0282
摘要
Background: Spinal muscular atrophy (SMA) is traditionally molecularly diagnosed by multiplex ligation-dependent probe amplification or quantitative polymerase chain reaction (qPCR). SMA analyses are not routinely incorporated into gene panel analyses for individuals with suspected SMA or broader neuromuscular indications. Aim: We sought to determine whether a next-generation sequencing (NGS) approach that integrates SMA analyses into a multigene neuromuscular disorders panel could detect undiagnosed SMA. Materials and Methods: Sequence and copy number variants of the SMN1/SMN2 genes were simultaneously analyzed in samples from 5304 unselected individuals referred for testing using an NGS-based 122-gene neuromuscular panel. This diagnostic approach was validated using DNA from 68 individuals who had been previously diagnosed with SMA via quantitative PCR for SMN1/SMN2. Results: Homozygous loss of SMN1 was detected in 47 unselected individuals. Heterozygous loss of SMN1 was detected in 118 individuals; 8 had an indeterminate variant in “SMN1 or SMN2” that supported an SMA diagnosis but required additional disambiguation. Of the remaining SMA carriers, 44 had pathogenic variants in other genes. Concordance rates between NGS and qPCR were 100% and 93% for SMN1 and SMN2 copy numbers, respectively. Where there was disagreement, phenotypes were more consistent with the SMN2 results from NGS. Conclusion: Integrating NGS-based SMA testing into a multigene neuromuscular panel allows a single assay to diagnose SMA while comprehensively assessing the spectrum of variants that can occur in individuals with broad differential diagnoses or nonspecific/overlapping neuromuscular features.
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