Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
Genet Med. 2021 Aug;23(8):1569-1573. doi: 10.1038/s41436-021-01174-1. Epub 2021 Apr 12.
Expansions of a subset of short tandem repeats (STRs) have been implicated in approximately 30 different human genetic disorders. Despite extensive application of exome sequencing (ES) in routine diagnostic genetic testing, STRs are not routinely identified from these data.
We assessed diagnostic utility of STR analysis in exome sequencing by applying ExpansionHunter to 2,867 exomes from movement disorder patients and 35,228 other clinical exomes.
We identified 38 movement disorder patients with a possible aberrant STR length. Validation by polymerase chain reaction (PCR) and/or repeat-primed PCR technologies confirmed the presence of aberrant expansion alleles for 13 (34%). For seven of these patients the genotype was compatible with the phenotypic description, resulting in a molecular diagnosis. We subsequently tested the remainder of our diagnostic ES cohort, including over 30 clinically and genetically heterogeneous disorders. Optimized manual curation yielded 167 samples with a likely aberrant STR length. Validations confirmed 93/167 (56%) aberrant expansion alleles, of which 48 were in the pathogenic range and 45 in the premutation range.
Our work provides guidance for the implementation of STR analysis in clinical ES. Our results show that systematic STR evaluation may increase diagnostic ES yield by 0.2%, and recommend making STR evaluation a routine part of ES interpretation in genetic testing laboratories.
短串联重复序列（STRs）的扩展与大约 30 种不同的人类遗传疾病有关。尽管外显子组测序（ES）在常规诊断性遗传检测中得到了广泛应用，但这些数据通常不会识别 STRs。
我们通过将 ExpansionHunter 应用于 2867 个运动障碍患者的外显子组和 35228 个其他临床外显子组，评估了 STR 分析在外显子组测序中的诊断效用。
我们鉴定出 38 名可能存在异常 STR 长度的运动障碍患者。通过聚合酶链反应（PCR）和/或重复引物 PCR 技术的验证证实了 13 名患者（34%）存在异常扩增等位基因。对于其中 7 名患者，基因型与表型描述相符，导致分子诊断。随后，我们对我们的诊断性 ES 队列的其余部分进行了测试，包括 30 多种临床和遗传上异质的疾病。优化的手动注释产生了 167 个可能存在异常 STR 长度的样本。验证证实了 93/167（56%）异常扩增等位基因，其中 48 个处于致病性范围，45 个处于前突变范围。
我们的工作为临床 ES 中 STR 分析的实施提供了指导。我们的结果表明，系统的 STR 评估可以使诊断性 ES 的产量增加 0.2%，并建议在遗传检测实验室中，将 STR 评估作为 ES 解释的常规部分。
