North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.
Prenat Diagn. 2022 Jun;42(7):831-844. doi: 10.1002/pd.6165. Epub 2022 May 7.
Prenatal exome sequencing (ES) for monogenic disorders in fetuses with structural anomalies increases diagnostic yield. In England there is a national trio ES service delivered from two laboratories. To minimise incidental findings and reduce the number of variants investigated, analysis uses a panel of 1205 genes where pathogenic variants may cause abnormalities presenting prenatally. Here we review our laboratory's early experience developing and delivering ES to identify challenges in interpretation and reporting and inform service development.
A retrospective laboratory records review from 01.04.2020 to 31.05.2021.
Twenty-four of 116 completed cases were identified as challenging including 13 resulting in difficulties in analysis and reporting, nine where trio inheritance filtering would have missed the diagnosis, and two with no prenatal diagnosis; one due to inadequate pipeline sensitivity, the other because the gene was not on the panel. Two cases with copy number variants identified were not detectable by microarray.
Variant interpretation requires close communication between referring clinicians, with occasional additional examination of the fetus or parents and communication of evolving phenotypes. Inheritance filtering misses ∼5% of diagnoses. Panel analysis reduces but does not exclude incidental findings. Regular review of published literature is required to identify new reports that may aid classification.
对存在结构异常的胎儿进行单基因疾病的产前外显子组测序 (ES) 可提高诊断率。在英国，有一个由两个实验室提供的全国性三托架 ES 服务。为了尽量减少偶然发现并减少要研究的变异数量，分析使用了一个可能导致产前出现异常的 1205 个基因的面板。在这里，我们回顾了我们实验室在开发和提供 ES 方面的早期经验，以发现解释和报告方面的挑战，并为服务开发提供信息。
对 2020 年 4 月 1 日至 2021 年 5 月 31 日的实验室记录进行回顾性分析。
在 116 例已完成的病例中，有 24 例被认为具有挑战性，其中 13 例导致分析和报告困难，9 例三托架遗传过滤会错过诊断，2 例无产前诊断；1 例是由于流水线敏感性不足，另 1 例是因为该基因不在面板上。有 2 例经微阵列检测到的拷贝数变异无法检测到。
变异解释需要参考临床医生之间的密切沟通，偶尔还需要对胎儿或父母进行额外检查，并对不断变化的表型进行沟通。遗传过滤会错过约 5%的诊断。面板分析减少但不能排除偶然发现。需要定期审查已发表的文献，以识别可能有助于分类的新报告。
