The prevalence of genetic diagnoses in fetuses with severe congenital heart defects

Abstract

Purpose: Congenital heart defects (CHD) are associated with genetic syndromes. Rapid aneuploidy testing and chromosome microarray analysis (CMA) are standard care in fetal CHD. Many genetic syndromes remain undetected with these tests. This cohort study aims to estimate the frequency of causal genetic variants, in particular structural chromosome abnormalities and sequence variants, in fetuses with severe CHD at mid-gestation, to aid prenatal counselling. Methods: Fetuses with severe CHD were extracted from the PRECOR registry (2012-2016). We evaluated pre-and postnatal genetic testing results retrospectively to estimate the frequency of genetic diagnoses in general, as well as for specific CHDs. Results: 919 fetuses with severe CHD were identified. After exclusion of 211 cases with aneuploidy, a genetic diagnosis was found in 15.7% (111/708). These comprised copy number variants in 9.9% (70/708). In 4.5% (41/708) sequence variants were found that would have remained undetected with CMA. Interrupted aortic arch, pulmonary atresia with ventricular septal defect and atrioventricular septal defect were most commonly associated with a genetic diagnosis. Conclusion: In case of normal CMA results, parents should be offered exome sequencing sequentially, if time allows for it, especially if the CHD is accompanied by other structural malformations due to the large variety in genetic syndromes.

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

“…Non-genetic causes are identified in only 2% of CHD cases, whereas a genetic cause can be identified in 20-30% of CHD patients 3 . Although most CHD can be repaired, achieving good long-term outcome as a consequence of optimized medical and surgical care, the prognosis remains poor for the majority with associated genetic abnormalities 4,5 . Therefore, prenatal definition of a genetic abnormality at the time of a CHD diagnosis is important, in order to provide accurate and appropriate counseling that will inform parental decisions regarding continuation or termination of the pregnancy as well as guiding prenatal surveillance and perinatal care.…”

Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives—A Systematic Review

“… 6-case study because it investigated a very specific phenotype after negative panel [ 78 ]. 708-case study due to the postnatal diagnosis [ 79 ]. …”

Beyond diagnostic yield: prenatal exome sequencing results in maternal, neonatal, and familial clinical management changes

“…For example, parents of a baby with an isolated heart defect detected on ultrasound are more likely to terminate their pregnancy if an underlying genetic condition is identified. 38 As this decision is restricted to the prenatal period, access to prenatal genetic testing including pES is imperative for parents to make informed decisions about their pregnancy.…”