Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, U.S.A.
Texas Children's Hospital, 6621 Fannin Street, Houston, Texas, 77030, U.S.A.
Clin Genet. 2013 May;83(5):457-461. doi: 10.1111/j.1399-0004.2012.01951.x. Epub 2012 Sep 11.
The advent of whole-exome next-generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½-year old female patient with a 2-year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work-up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di-deoxy sequencing. WES revealed a de novo non-synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.
全外显子组下一代测序（WES）的出现对孟德尔疾病的分子特征分析具有重要意义；然而，WES 的临床适用性仍未得到充分探索。我们描述了对一位 3 岁半女性患者的探索性研究，该患者 2 年来间歇性出现肌肉无力和阵发性抽搐，此前曾进行过广泛但未发现异常的诊断性检查。对先证者及其父母进行了 WES 检测。利用父母外显子组数据来筛选先证者中潜在的新生基因组事件，并通过双脱氧测序来验证可疑变异。WES 发现钙通道基因 CACNA1S 外显子 21 上存在新生错义突变，该突变曾在单个患者中被报道为罕见的非典型低钾周期性瘫痪的原因。这令人意外，因为先证者最初的鉴别诊断包括低钾周期性瘫痪，但临床和实验室特征不明确，低钾周期性瘫痪及相关疾病的标准临床分子检测为阴性。本报告强调了 WES 在临床实践中的潜在诊断价值，对未来类似的诊断难题的处理方法具有启示意义。
