Learning to Crawl: Determining the Role of Genetic Abnormalities on Postoperative Outcomes in Congenital Heart Disease

Abstract

Background Our cardiac center established a systematic approach for inpatient cardiovascular genetics evaluations of infants with congenital heart disease, including routine chromosomal microarray (CMA) testing. This provides a new opportunity to investigate correlation between genetic abnormalities and postoperative course. Methods and Results Infants who underwent congenital heart disease surgery as neonates (aged ≤28 days) from 2015 to 2020 were identified. Cases with trisomy 21 or 18 were excluded. Diagnostic genetic results or CMA with variant of uncertain significance were considered abnormal. We compared postoperative outcomes following initial congenital heart disease surgery in patients found to have genetic abnormality to those who had negative CMA. Among 355 eligible patients, genetics consultations or CMA were completed in 88%. A genetic abnormality was identified in 73 patients (21%), whereas 221 had negative CMA results. Genetic abnormality was associated with prematurity, extracardiac anomaly, and lower weight at surgery. Operative mortality rate was 9.6% in patients with a genetic abnormality versus 4.1% in patients without an identified genetic abnormality ( P =0.080). Mortality was similar when genetic evaluations were diagnostic (9.3%) or identified a variant of uncertain significance on CMA (10.0%). Among 14 patients with 22q11.2 deletion, the 2 mortality cases had additional CMA findings. In patients without extracardiac anomaly, genetic abnormality was independently associated with increased mortality ( P =0.019). CMA abnormality was not associated with postoperative length of hospitalization, extracorporeal membrane oxygenation, or >7 days to initial extubation. Conclusions Routine genetic evaluations and CMA may help to stratify mortality risk in severe congenital heart disease with syndromic or nonsyndromic presentations.

A Multicenter Analysis of Abnormal Chromosomal Microarray Findings in Congenital Heart Disease

“…Recent studies indicate that CNVs may impact survival in patients with nonsyndromic presentations. 35 , 36 Taken together, these data point to a critical role for copy number analysis in the genetic classification of study cohorts with severe CHD.…”

Genome Sequencing is Critical for Forecasting Outcomes following Congenital Cardiac Surgery

“…Established and emerging literature has highlighted the impact of genetics on mortality and other adverse outcomes following congenital cardiac surgery, mostly focusing on the impact of copy number variants. [10][11][12][13][14] Damaging de novo genic variants were associated with worse transplant-free survival and longer times to final extubation in a previously reported subset of the PCGC cohort (n = 1268) 10 . Here, we expand upon these findings in the largest study to date relating genotypes to CHD surgical outcomes.…”

“…Recent work has also demonstrated the value of genetic testing for outcomes prediction for specific types of CHD and within specific clinical contexts [10][11][12][13][14] . Broader investigations, however, have faced difficulties in assaying genetic contributions across multiple CHD phenotypes and clinical contexts, in part due to the widely varying severity of CHD lesions and the complex medical and surgical interventions necessary for survival.…”

Rapid Genome Sequencing Shows Diagnostic Utility In Infants With Congenital Heart Defects

“…20 Additionally, studies demonstrate CMA can be utilized to identify genotype-phenotype associations in CHD. 21 However, recently the genetic testing landscape has seen a shift to newer modalities including genome sequencing.…”