Prenatal exome sequencing in fetuses with congenital heart defects

Clin Genet. 2020 Sep;98(3):215-230. doi: 10.1111/cge.13774. Epub 2020 Jun 9.


The genetic diagnosis of congenital heart defects (CHDs) is challenging because of genetic and phenotypic heterogeneity. The aim of our study was to evaluate the clinical value of whole exome sequencing (WES) in the prenatal diagnosis of CHDs in a large cohort. Trio-based WES was performed in 260 fetuses with CHDs negative for karyotype and chromosome microarray analysis results. WES produced a diagnostic yield of 10% (26/260) in the entire cohort. Relative high diagnostic rate was observed in cases with cardiac rhabdomyoma (60%), complex CHDs (16.7%), septal defect (14.0%), and conotruncal defect (9.9%). There was no significant difference between the diagnostic yields in simple and complex CHDs groups (9.9% vs 16.7%), and in non-isolated and isolated CHDs groups (15.7% vs 7.9%). The diagnostic yields in cases with CHDs with soft markers, CHDs with fetal growth restriction, and CHDs with other structural anomalies (syndromic CHDs) were 0 (0/13), 50% (1/2) and 18.2% (10/55), respectively. Variants of unknown significance were detected in 16 (6.2%) fetuses, and secondary findings in 7 (2.7%) cases. Variants in 14 candidate genes were identified. Our study demonstrates an incremental diagnostic yield by trio-based WES in the prenatal diagnosis of CHDs after routine tests, not as high as expected.

Keywords: congenital heart defect; diagnostic yield; exome sequencing; prenatal diagnosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Aberrations
  • Exome Sequencing
  • Female
  • Fetus
  • Gestational Age
  • Heart Defects, Congenital / classification
  • Heart Defects, Congenital / diagnosis*
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / pathology
  • Heart Septal Defects / diagnosis*
  • Heart Septal Defects / genetics
  • Heart Septal Defects / pathology
  • Humans
  • Karyotype
  • Pregnancy
  • Prenatal Diagnosis*
  • Rhabdomyoma / diagnosis*
  • Rhabdomyoma / genetics
  • Rhabdomyoma / pathology

Supplementary concepts

  • Conotruncal cardiac defects