Congenital Heart Disease and the Diagnostic Yield with Exome Sequencing (CODE Study): Prospective Cohort Study and Systematic Review


To determine the yield of antenatal exome sequencing (ES) over chromosome microarray (CMA) / conventional karyotyping in; (i) any prenatally diagnosed congenital heart disease (CHD); (ii) isolated CHD; (iii) multi-system CHD and; (iv) CHD by phenotypic subgroup.


A prospective cohort study of 197 trios undergoing ES following CMA/karyotype because CHD was identified prenatally and a systematic review of the literature was performed. MEDLINE, EMBASE and CINAHL (2000-Oct 2019) databases were searched electronically. Selected studies included those with; (i) >3 cases; (ii) initiation of testing based upon a prenatal phenotype only and; (iii) where CMA/karyotyping was negative. PROSPERO No. CRD42019140309


In our cohort ES gave an additional diagnostic yield in; (i) all CHD; (ii) isolated CHD and; (iii) multi-system CHD of 12.7% (n=25/197), 11.5% (n=14/122) and 14.7% (n=11/75) (p=0.81). The pooled incremental yields for the aforementioned categories from 18-studies (n=636) were 21% (95% CI, 15-27%), 11% (95% CI, 7-15%) and 37% (95% CI, 18%-56%) respectively. This did not differ significantly when sub-analyses were limited to studies including >20 cases. In instances of multi-system CHD in the primary analysis, the commonest extra-cardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system 44.2% (n=23/52). Cardiac shunt lesions had the greatest incremental yield, 41% (95% CI, 19-63%), followed by right-sided lesions 26% (95% CI, 9-43%). In the majority of instances pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes (68/96; 70.8%). The commonest monogenic syndrome identified was Kabuki syndrome (n=19/96; 19.8%).


Despite the apparent incremental yield of prenatal exome sequencing in congenital heart disease, the routine application of such a policy would require the adoption of robust bioinformatic, clinical and ethical pathways. Whilst the greatest yield is with multi-system anomalies, consideration may also be given to performing ES in the presence of isolated cardiac abnormalities.