Exome sequencing for perinatal phenotypes: The significance of deep phenotyping
Exome sequencing for perinatal phenotypes: The significance of deep phenotyping
复制标题
DOI：
10.1002/pd.5616
复制
发表时间：
2019-12-05
影响因子：
3
通讯作者：
Dalal, Ashwin
中科院分区：
文献类型：
--
作者：
Aggarwal, Shagun;Vineeth, Venugopal Satidevi;Dalal, Ashwin
目的 确定外显子组测序（ES）技术在确定围产期异常表型病因学基础方面的性能，并研究综合表型分析对变异优先顺序的影响。方法 精心挑选的 32/204 名在死后/产后深度表型分析后具有异常围产期表型的胎儿接受 ES 以确定胎儿表型的致病变异。在 Phenolyzer 软件的帮助下，对产前与死后/产后基于表型的变异优先顺序进行了回顾性比较分析。我们对选定的文献报告进行了回顾，以检查这些报告中病例表型信息的完整性以及它如何影响胎儿 ES 的表现。结果 在 18/32 (56%) 的胎儿中，鉴定出致病性/可能致病性变异。这包括新的基因型-表型关联、已知孟德尔疾病的产前表型扩展和双重孟德尔诊断。回顾性分析显示，在 15/22 (68%) 的病例中，仅根据产前检查结果无法识别推定的诊断变异，这表明综合死后/产后表型信息的重要性。文献综述支持这些发现，但由于所涉及研究的明显异质性，无法得出结论。结论 综合表型分析对于提高 ES 围产期队列的诊断性能和促进新基因型-表型关联的识别至关重要。
Objective To ascertain the performance of exome sequencing (ES) technology for determining the etiological basis of abnormal perinatal phenotypes and to study the impact of comprehensive phenotyping on variant prioritization. Methods A carefully selected cohort of 32/204 fetuses with abnormal perinatal phenotypes following postmortem/postnatal deep phenotyping underwent ES to identify a causative variant for the fetal phenotype. A retrospective comparative analysis of the prenatal versus postmortem/postnatal phenotype-based variant prioritization was performed with aid of Phenolyzer software. A review of selected literature reports was done to examine the completeness of phenotypic information for cases in those reports and how it impacted the performance of fetal ES. Results In 18/32 (56%) fetuses, a pathogenic/likely pathogenic variant was identified. This included novel genotype-phenotype associations, expanded prenatal phenotypes of known Mendelian disorders and dual Mendelian diagnoses. The retrospective analysis revealed that the putative diagnostic variant could not be identified on basis of prenatal findings alone in 15/22 (68%) cases, indicating the importance of comprehensive postmortem/postnatal phenotype information. Literature review was supportive of these findings but could not be conclusive due to marked heterogeneity of involved studies. Conclusion Comprehensive phenotyping is essential for improving diagnostic performance and facilitating identification of novel genotype-phenotype associations in perinatal cohorts undergoing ES.