Diagnostic yield of whole exome data in fetuses aborted for conotruncal malformations

Abstract

Objective We investigated a custom congenital heart disease (CHD) geneset to assess the diagnostic value of whole‐exome sequencing (WES) in karyotype‐ and copy number variation (CNV)‐negative aborted fetuses with conotruncal defects (CTDs), and to explore the impact of postnatal phenotyping on genetic diagnosis. Methods We sequentially analyzed CNV‐seq and WES data from 47 CTD fetuses detected by prenatal ultrasonography. Fetuses with either a confirmed aneuploidy or pathogenic CNV were excluded from the WES analyses, which were performed following the American College of Medical Genetics and Genomics recommendations and a custom CHD‐geneset. Imaging and autopsy were applied to obtain postnatal phenotypic information about aborted fetuses. Results CNV‐seq identified aneuploidy in 7/47 cases while 13/47 fetuses were CNV‐positive. Eighty‐five rare deleterious variants in 61 genes (from custom geneset) were identified by WES in the remaining 27 fetuses. Of these, five pathogenic or likely pathogenic variants (PV/LPV) were identified in five fetuses, revealing a 10.6% (5/47) incremental diagnostic yield. Furthermore, RERE:c.2461_2472delGGGATGTGGCGA was reclassified as LPV based on postnatal phenotypic data. Conclusion We have developed and defined a CHD gene panel that can be utilized in a subset of fetuses with CTDs. We demonstrate the utility of incorporating both prenatal and postnatal phenotypic information may facilitate WES diagnostics.

Diagnostic yield after next-generation sequencing in pediatric cardiovascular disease

“…Many other studies have focused on fetuses that were diagnosed in the prenatal period (for example, Shi et al. 27 and Sun et al. 28 ) in whom extracardiac anomalies may be more difficult to appreciate and the generalizability of diagnostic rates is not known.…”

Relationship between diagnosis of conus arteriosus malformation and genetic diagnosis results in fetal cardiac axis abnormalities by echocardiography during middle pregnancy

“…Genetic testing: Low depth whole genome and whole exome sequencing technology were used for diagnosis by amniotic fluid puncture ( 10 ). Low depth whole genome sequencing refers to the use of high throughput sequencing technology to conduct low depth whole genome sequencing of sample DNA, compare the sequencing results with the human reference genome base sequence, and detect the presence of CNVs in the tested sample through biological information analysis ( 11 ).Among them, fetal cardiac axis abnormalities were considered positive for genetic results due to factors such as aneuploidy, copy number abnormalities, and single-gene pathogenicity.…”

The evolving genetic etiology of conotruncal anomalies

“…1 Within this group of conotruncal anomalies, the rate of genetic diagnoses antenatally is 17%-26%. 12 The detection rate varies according to the condition being studied. 3,4 The commonest genetic findings in patients with conotruncal defects are trisomy 13, trisomy 18, trisomy 21 and 22q11.21 deletion.…”

“…Conotruncal heart malformations are a heterogenous group of abnormalities of the cardiac outflow tract, representing approximately 20% of all antenatally detected cardiac anomalies 1 . Within this group of conotruncal anomalies, the rate of genetic diagnoses antenatally is 17%–26% 12 . The detection rate varies according to the condition being studied 3,4 .…”