Contribution of single‐gene defects to congenital cardiac left‐sided lesions in the prenatal setting

Abstract

Objectives To explore the contribution of single‐gene defects to the genetic cause of cardiac left‐sided lesions (LSLs), and to evaluate the incremental diagnostic yield of whole‐exome sequencing (WES) for single‐gene defects in fetuses with LSLs without aneuploidy or a pathogenic copy‐number variant (pCNV). Methods Between 10 April 2015 and 30 October 2018, we recruited 80 pregnant women diagnosed with a LSL who had termination of pregnancy and genetic testing. Eligible LSLs were aortic valve atresia or stenosis, coarctation of the aorta, mitral atresia or stenosis and hypoplastic left heart syndrome (HLHS). CNV sequencing (CNV‐seq) and WES were performed sequentially on specimens from these fetuses and their parents. CNV‐seq was used to identify aneuploidies and pCNVs, while WES was used to identify diagnostic genetic variants in cases without aneuploidy or pCNV. Results Of 80 pregnancies included in the study, 27 (33.8%) had a genetic diagnosis. CNV‐seq analysis identified six (7.5%) fetuses with aneuploidy and eight (10.0%) with pCNVs. WES analysis of the remaining 66 cases revealed diagnostic genetic variants in 13 (19.7%) cases, indicating that the diagnostic yield of WES for the entire cohort was 16.3% (13/80). KMT2D was the most frequently mutated gene (7/66 (10.6%)) in fetuses with LSL without aneuploidy or pCNVs, followed by NOTCH1 (4/66 (6.1%)). HLHS was the most prevalent cardiac phenotype (4/7) in cases with a KMT2D mutation in this cohort. An additional six (9.1%) cases were found to have potentially deleterious variants in candidate genes. Conclusions Single‐gene defects contribute substantially to the genetic etiology of fetal LSLs. KMT2D mutations accounted for approximately 10% of LSLs in our fetal cohort. WES has the potential to provide genetic diagnoses in fetuses with LSLs without aneuploidy or pCNVs. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal exome sequencing in fetuses with congenital heart defects

“…Recent study by Sun et al specialized on prenatal cardiac leftsided lesions revealed diagnostic variants in 19.7% (13/66) cases, and found that KMT2D mutation occurred in 10.6% (7/66) of cases. 17 However, in this study, the diagnostic yield in left heart defect subgroup was relatively low (7.9%, 3/38). Only one fetus with a de novo truncating mutation in KMT2D gene was identified, presenting mitral atresia and absence of aortic valve.…”

“…In the study of Sun et al, only fetuses with cardiac leftsided lesions leading to termination of pregnancy were recruited which could represent more severe phenotypes, and 60% cases were hypoplastic left heart syndrome (HLHS). 17 While in our study, 78.9%…”

“…Previous WES studies on fetuses with CHDs, including both trio and fetus only samples, have been reported in a relative small sample size with diagnostic rates varying between 5.2% and 23.1%. [11][12][13][14][15][16][17] In the present study, we performed trio-based WES analysis of 260 fetuses with CHDs in a large cohort. Diagnostic variants were obtained in 10% (26/260) of the cases, very close to the diagnostic rate (11.1%, 9/81) in CHDs from Lord's report, which was the largest prenatal exome sequencing research to date.…”

“…16 Another study specialized on congenital cardiac left-sided lesions in prenatal setting revealed diagnostic variants in 19.7% (13/66) cases. 17 In this study, we performed WES analysis in 260 fetuses with CHDs, with or without other ultrasound anomalies but negative karyotype and CMA results, and evaluate its clinical value in prenatal diagnosis. The diagnostic yields of WES in different CHD subgroups were investigated in detail.…”

A novel de novo dominant mutation of NOTCH1 gene in an Iranian family with non‐syndromic congenital heart disease

“…New approaches such as NGS can provided CHD genetic etiology. 25 Our study indicates the first novel de novo germline mutation identified by WES in an Iranian family with different types of CHD. Although we surveyed nine likely pathogenic variants in the family members but none of them were completely segregated except one, c.T6797C in the NOTCH1 gene, and this illustrates the complexity of the CHD causing identification.…”