P379: Defect detect: Evaluating diagnostic rates of genetic testing in infants with congenital heart defects

Introduction: Congenital heart defects (CHDs) are the most prevalent congenital anomaly, accounting for approximately one-third of all major congenital anomalies and affecting around 1% of live births.CHDs are divided into syndromic (involvement of other organ systems) and non-syndromic (involvement of cardiac system only).Historically, genetic testing has been primarily utilized in the work-up of syndromic CHDs but there are important and identifiable genetic etiologies to both syndromic and non-syndromic CHDs that can have implications for the affected individual's medical management and the family's reproductive risk.The American College of Medical Genetics and Genomics recommends consideration of exome or genome sequencing (ES/GS) as first-line genetic testing in the evaluation of pediatric patients with congenital anomalies, but SNV chromosomal microarrays often remain the most performed initial genetic testing for individuals with CHDs.Methods: This study aims to evaluate the diagnostic rates for various genetic tests in a cohort of patients with syndromic and non-syndromic complex CHDs from 2020-2024 at UPMC Children's Hospital of Pittsburgh.Retrospective chart review was performed on 187 infants who were seen by the inpatient Medical Genetics team between 2020-2024 for evaluation of their CHD.The primary goal of this study was to summarize the types of genetic testing types (eg, SNV chromosomal microarrays, CHD gene panels, and exome/genome sequencing, etc) and results in this population.This study was approved through the University of Pittsburgh's IRB (Study 24070029).Results: The CHDs were considered syndromic in 42% (79/187) individuals.At least one diagnostic genetic test was performed in 97% (181/187) of cases; six families declined any testing including one syndromic CHD.A genetic explanation for the CHD was found in 18% (33/181) with a diagnostic rate of 33% (26/78) in syndromic cases vs 7% (7/103) in cases that were apparently non-syndromic at time of initial evaluation.Of these seven non-syndromic cases, three had monogenic etiologies that were associated with isolated CHD (PLD1, RBFOX2, ZFPM2), three had 22q11.2deletion syndrome, and one had mosaic Turner syndrome.SNV chromosomal microarray was the most common initial test performed in 94% (171/181) of cases and yielded an explanation for the CHD in 12% (20/171) with 22q11.2deletion syndrome being the most common diagnosis (9/20).Outpatient follow-up and/or further sequence-based testing while still inpatient was recommended after negative and/or non-diagnostic SNV chromosomal microarray but only 44% (66/151) had additional testing with 14% (9/66) receiving a diagnosis on a gene panel (1/9) or ES/GS (8/9).An additional four diagnoses were made based on physical exam and clinical criteria.Other results from testing included variants of uncertain significance (VUS) in 31% (57/181) cases with 32 of those VUS being identified on the initial SNV chromosomal microarray.Genetic diagnoses unrelated to the CHD were found in five cases including one secondary finding (Lynch syndrome).Conclusion: While SNV chromosomal microarrays remain the most recommended initial genetic test in our patient population with CHDs, their diagnostic yield alone is relatively low, and they may return with VUS that prompt further investigation with additional studies.Many families choose not to pursue further genetic testing and/or evaluation if initial testing is negative.Therefore, more comprehensive genetic testing methods (eg, ES/GS), which can identify copy number variants and single gene defects, should be considered and offered as first-line options to increase the diagnostic rate in infants with syndromic and apparently non-syndromic CHDs.