Abstract
The use of clinical genetics evaluations and testing for infants with congenital heart defects (CHDs) is subject to practice variation. This single-institution cross-sectional study of all inpatient infants with severe CHDs evaluated 440 patients using a cardiovascular genetics service (2014–2019). In total, 376 (85.5%) had chromosome microarray (CMA), of which 55 (14.6%) were diagnostic in syndromic (N = 35) or isolated (N = 20) presentations. Genetic diagnoses were made in all CHD classes. Diagnostic yield was higher in syndromic appearing infants, but geneticists’ dysmorphology exams lacked complete sensitivity and 6.5% of isolated CHD cases had diagnostic CMA. Interestingly, diagnostic results (15.8%) in left ventricular outflow tract obstruction (LVOTO) defects occurred most often in patients with isolated CHD. Geneticists’ evaluations were particularly important for second-tier molecular testing (10.5% test-specific yield), bringing the overall genetic testing yield to 17%. We assess these results in the context of previous studies. Cumulative evidence provides a rationale for comprehensive, standardized genetic evaluation in infants with severe CHDs regardless of lesion or extracardiac anomalies because genetic diagnoses that impact care are easily missed. These findings support routine CMA testing in infants with severe CHDs and underscore the importance of copy-number analysis with newer testing strategies such as exome and genome sequencing.
Highlights
Congenital heart defects (CHDs) are the most prevalent type of birth defect, with an estimated global prevalence of ~1–2% [1,2]
Differences in the yields of testing are at least partially related to the increasing number of panels available over time. When considering those diagnoses that were confirmed via molecular genetic testing in addition to chromosome microarray (CMA), the overall diagnostic proportion in our study increased to approximately 17%
Cumulative evidence indicates that genetic testing is important in infants with critical CHDs requiring hospitalization in the first year of life
Summary
Congenital heart defects (CHDs) are the most prevalent type of birth defect, with an estimated global prevalence of ~1–2% [1,2]. CHD etiologies are diverse, and it is currently estimated that up to 20–30% of cases have an identifiable genetic or environmental etiology [3]. It is expected that the proportion of CHDs with an identifiable genetic cause will increase with the ongoing expansion of genomic testing. The remaining 60–80% of cases may be caused by novel genetic and epigenetic risk factors awaiting identification. Novel applications of exome and whole-genome sequencing (ES/WGS) are showing diagnostic yields ranging approximately 5–30% for CHDs. there is considerable variability in the methodology of CHD ES/WGS studies to date [4,5,6,7,8,9,10]
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