Comprehensive evaluation of genetic variants using chromosomal microarray analysis and exome sequencing in fetuses with congenital heart defect

Ultrasound Obstet Gynecol. 2021 Sep;58(3):377-387. doi: 10.1002/uog.23532.


Objective: To evaluate comprehensively, using chromosomal microarray analysis (CMA) and exome sequencing (ES), the prevalence of chromosomal abnormalities and sequence variants in unselected fetuses with congenital heart defect (CHD) and to evaluate the potential diagnostic yields of CMA and ES for different CHD subgroups.

Methods: This was a study of 360 unselected singleton fetuses with CHD detected by echocardiography, referred to our department for genetic testing between February 2018 and December 2019. We performed CMA, as a routine test for aneuploidy and copy number variations (CNV), and then, in cases without aneuploidy or pathogenic CNV on CMA, we performed ES.

Results: Overall, positive genetic diagnoses were made in 84 (23.3%) fetuses: chromosomal abnormalities were detected by CMA in 60 (16.7%) and sequence variants were detected by ES in a further 24 (6.7%) cases. The detection rate of pathogenic and likely pathogenic genetic variants in fetuses with non-isolated CHD (32/83, 38.6%) was significantly higher than that in fetuses with isolated CHD (52/277, 18.8%) (P < 0.001), this difference being due mainly to the difference in frequency of aneuploidy between the two groups. The prevalence of a genetic defect was highest in fetuses with an atrioventricular septal defect (36.8%), ventricular septal defect with or without atrial septal defect (28.4%), conotruncal defect (22.2%) or right ventricular outflow tract obstruction (20.0%). We also identified two novel missense mutations (c.2447G>C, p.Arg816Pro; c.1171C>T, p.Arg391Cys) and a new phenotype caused by variants in PLD1.

Conclusions: Chromosomal abnormalities were identified in 16.7% and sequence variants in a further 6.7% of fetuses with CHD. ES should be offered to all pregnant women with a CHD fetus without chromosomal abnormality or pathogenic CNV identified by CMA, regardless of whether the CHD is isolated. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Keywords: CNV; congenital heart defect; exome sequencing; prenatal diagnosis; sequence variants.

Publication types

  • Evaluation Study

MeSH terms

  • Adult
  • Aneuploidy
  • Chromosome Aberrations / classification
  • Chromosome Aberrations / embryology
  • DNA Copy Number Variations
  • Echocardiography
  • Exome Sequencing*
  • Female
  • Fetus / abnormalities*
  • Fetus / embryology
  • Genetic Variation
  • Heart Defects, Congenital / diagnosis*
  • Heart Defects, Congenital / embryology
  • Heart Defects, Congenital / genetics
  • Humans
  • Microarray Analysis*
  • Pregnancy
  • Prenatal Diagnosis / methods*
  • Prevalence
  • Ultrasonography, Prenatal