O0014: Yield of Systematic Inpatient Genetic Testing of Neonates with Conotruncal and Laterality Heart Defects

Background: Many studies have demonstrated a high yield of genetic testing in congenital heart disease (CHD); however, to date, testing in most centers is not systematic and performed in a clinical setting.

Methods: We performed a retrospective cohort study of infants with conotruncal and/or laterality CHD admitted to either the neonatal or cardiac intensive care units < 28 days of age between January 2012 - December 2019. During this time, institutional recommendations were for a chromosomal microarray (CMA) for all children with CHD if a clear diagnosis of aneuploidy was not present. If negative, gene panel or exome sequencing was considered for infants with dysmorphic features, extracardiac defects (ECA), or a family history of CHD. Results of prenatal and postnatal genetic testing were reported by CHD lesion, and by testing modality.

Results: A total of 697 subjects met inclusion criteria, with 51% of those with laterality CHD. A total of 94% (n=655) had at least one form of genetic testing, with 96% of those having had a CMA prenatally or postnatally. Overall yield of systematic genetic testing was 19% (123/655) for a pathogenic diagnostic finding, with 30% of conotruncal CHD, and 7% of laterality CHD subjects. Chromosomal anomalies and copy number variants were present in 27% of conotruncal anomalies, with the most common changes being 22q11.2 deletion (14%), followed by trisomy 21 (5%); and 4% of laterality defects, with the most common being trisomy 21 (13%). Gene sequencing was done in 16% of those with conotruncal CHD, and 15% of those with laterality defects, of which the pathogenic diagnostic yield was 20% and 23% respectively. In subjects with conotruncal CHD, the most common detected change was of CHD7 sequence variants (9%), while the vast majority of changes in laterality defects were of sequence changes in ciliary and patterning genes (9%).

Conclusion: Systemic genetic testing of neonates with CHD consisting predominantly of CMA results in a high diagnostic rate for pathogenic genetic conditions for those with conotruncal defects. Given the high yield of gene sequencing in the minority of subjects tested with both conotruncal and laterality CHD, increased use of sequencing when CMA is negative is likely to provide even higher diagnostic rates.