Nonsyndromic Congenital Heart Disease Panel

Congenital heart disease (CHDs) encompasses a wide range of syndromic and non-syndromic conditions that feature structural abnormalities of the heart that arise during development. Nonsyndromic CHD is one of the most common birth defects and occurs in 1-3% of live births (Hoffman and Kaplan. 2002. PubMed ID: 12084585; van der Linde et al. 2011. PubMed ID: 22078432). Structural defects can include (but are not limited to): conotruncal abnormalities (tetralogy of Fallot, double-outlet right ventricle (DORV), truncus arteriosus, transposition of the great arteries (TGA), left ventricular outflow tract obstruction (coarctation of the aorta, aortic valve stenosis, bicuspid aortic valve, hypoplastic left heart), and septal defects. CHDs most commonly present as isolated structural defects of the heart; however, they can also present as part of a syndrome.

Recurrence risk for nonsyndromic CHDs is difficult to assess due to reduced penetrance, variable expressivity, environmental factors, and oligo/polygenic inheritance. Epidemiological studies suggest the recurrence risk for 1st degree relatives is ~3% and increases if a parent or two or more siblings are affected (5-10%) (Nora et al. 1994. PubMed ID: 8176108; Gill et al. 2003. PubMed ID: 12957444; Calcagni et al. 2007. PubMed ID: 17091259). However, recurrence risk varies by type of defect (Chaix et al. 2016. PubMed ID: 26981213) and is much higher in monogenic forms of CHDs.

Improved surgical and medical interventions has resulted in increasing prevalence of CHDs in adults. Determining the genetic etiology of CHDs allows for the identification of potential unanticipated extracardiac involvement, assess recurrence risk in future pregnancies, and can provide a more accurate prognosis.

CHDs can be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) manners. Nonsyndromic CHDs have been associated with both genetic (monogenic and oligo/polygenic) and environmental causes. Currently the genetic landscape of syndromic CHDs is better understood than nonsyndromic CHDs. Consistent with this, de novo variants have been found to contribute to ~8% of nonsyndromic CHD cases compared to 28% of CHD cases with extra cardiac anomalies (Jin et al. 2017. PubMed ID: 28991257; Homsy et al. 2015. PubMed ID: 26785492). The causes of monogenic forms of nonsyndromic CHDs are many and varied, but some of the most common include transcription factors important for heart development (NKX2-5, GATA4-6, HAND1, TBX1), notch signaling (JAG1, NOTCH1/2), and structural proteins (ACTC1, MYH7, ELN).  A wide range of genetic abnormalities, including aneuploidy (Down syndrome, Turner syndrome), chromosomal rearrangements, copy number variation (22q11.2 deletion syndrome, Williams-Beuren syndrome, Jacobsen syndrome, etc.), single nucleotide variants (SNVs), and insertions/deletions have been associated with CHDs.

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

The exact sensitivity of this panel is not known; however, sensitivity in nonsyndromic CHD is lower than syndromic forms. For isolated CHDs exome sequencing studies have found pathogenic variants in 16-20% of cases compared to 30-39% in syndromic forms (Alankarage et al. 2019. PubMed ID: 30293987; Shikany et al. 2020. PubMed ID: 32717230). Additionally, studies of large copy number variants (CNVs) using karyotype and chromosomal microarray have found pathogenic CNVs in ~6% of isolated cases compared to 26% in those with extra cardiac anomalies (Turan et al. 2018. PubMed ID: 29306563).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.1% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Please note that due to the presence of multiple pseudogenes, exons 1-4 of NOTCH2 are not covered by this test.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).