Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia.
Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia.
Genet Med. 2019 May;21(5):1111-1120. doi: 10.1038/s41436-018-0296-x. Epub 2018 Oct 8.
Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients.
Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband-parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines.
Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families.
Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.
先天性心脏病（CHD）影响了多达 1%的活产儿。然而，在大多数情况下并未做出基因诊断。本研究旨在评估对 CHD 患者异质队列进行基因组测序（GS）的结果。
招募了 97 个有先证者因 CHD 需要手术矫正的家庭进行基因组测序。每个家庭至少对一个先证者-父母三进行测序。GS 数据通过两级方法进行分析：应用高可信度基因筛选（hcCHD）和综合分析。使用美国医学遗传学与基因组学学会-分子病理学协会（ACMG-AMP）指南评估鉴定出的变异体的致病性。
在已知和新兴的 CHD 基因中鉴定出了具有临床意义的遗传变异体。hcCHD 筛选在 22%的家庭中发现了具有临床可操作性的变异体。随后的综合分析在具有近期疾病关联的基因中另外发现了 9%的家庭中具有临床可操作性的变异体。总的来说，这种两级方法为 31%的家庭提供了具有临床意义的变异体。
使用我们的两级方法分析 GS 数据，可以在我们的异质队列中确定三分之一具有高临床效用的变异体。然而，新兴基因与 CHD 病因的关联，以及用于变异体评估和解释的新技术的发展，将在未来重新评估我们的 GS 数据时提高诊断率。
