Congenital Structural Heart Disease Panel

62 gene panel that includes assessment of non-coding variants

Ideal for patients with congenital heart disease, particularly those with features of hereditary disorders. Is not ideal for patients suspected to have a ciliopathy or a rasopathy. For those patients, please consider our Primary Ciliary Dyskinesia Panel and our Noonan Syndrome Panel, respectively.

Analysis methods Availability Number of genes Test code CPT codes
4 weeks 62 GHC0009 SEQ 81405
SEQ 81406
SEQ 81407
DEL/DUP 81479


ICD codes
Commonly used ICD-10 code(s) when ordering the Congenital Structural Heart Disease Panel

Q21.3 Tetralogy of Fallot
Q87.2 Holt-Oram syndrome
Q25.3 Supravalvular aortic stenosis
Q44.7 Q44.7

Sample requirements:

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection. Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.


There are many types of congenital heart disease (CHD) ranging from simple asymptomatic defects to complex defects with severe, life-threatening symptoms. CHDs are the most common type of birth defect and affect at least 8 out of every 1,000 newborns. Annually, more than 35,000 babies in the United States are born with CHDs. Many of these CHDs are simple conditions and need no treatment or are easily repaired. Some babies are born with complex CHD requiring special medical care. The diagnosis and treatment of complex CHDs has greatly improved over the past few decades. As a result, almost all children who have complex heart defects survive to adulthood and can live active, productive lives. However, many patients who have complex CHDs continue to need special heart care throughout their lives. In the United States, more than 1 million adults are living with congenital heart disease.

Panel Content

Genes in the Comprehensive Cardiology Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABL1Congenital heart defects and skeletal malformations syndrome (CHDSKM)AD303
ACTA2Aortic aneurysm, familial thoracic, Moyamoya disease, Multisystemic smooth muscle dysfunction syndromeAD2072
ACTB*Baraitser-Winter syndromeAD4654
ACTC1Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Atrial septal defect, Dilated cardiomyopathy (DCM)AD2360
ACTG1Deafness, Baraitser-Winter syndromeAD2543
ACVR1Fibrodysplasia ossificans progressivaAD1419
ACVR2BHeterotaxy, visceral, 4, autosomalAD12
ADAMTS10Weill-Marchesani syndromeAR813
ADAMTS17Weill-Marchesani-like syndromeAR67
B3GAT3Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defectsAR513
BCORMicrophthalmia, syndromic, Oculofaciocardiodental syndromeXL3850
BMPR2Pulmonary hypertension, primary, Pulmonary venoocclusive diseaseAD386417
CBLNoonan syndrome-like disorder with or without juvenile myelomonocytic leukemiaAD2338
CDK13Congenital heart defects, dysmorphic facial features, and intellectual developmental disorderAD1313
CHD4Epilepsy, hearing loss, and mental retardation syndrome; EHLMRSAD1416
CHD7Isolated gonadotropin-releasing hormone deficiency, CHARGE syndromeAD244813
CRELD1Atrioventricular septal defect, partial, with or without heterotaxyAD16
CTC1Cerebroretinal microangiopathy with calcifications and cystsAR1630
DHCR7Smith-Lemli-Opitz syndromeAR67216
EFTUD2Mandibulofacial dysostosis with microcephaly, Esophageal atresia, syndromicAD4393
EIF2AK4Pulmonary venoocclusive diseaseAR2768
ELNCutis laxa, Supravalvular aortic stenosisAD72105
ENGJuvenile polyposis syndrome, Hereditary hemorrhagic telangiectasiaAD120478
FLNAFrontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defectsXL119235
GATA4Tetralogy of Fallot, Atrioventricular septal defect, Testicular anomalies with or without congenital heart disease, Ventricular septal defect, Atrial septal defectAD36126
GATA5Familial atrial fibrillation, Tetralogy of Fallot, Single ventricular septal defectAD/AR531
GATA6Heart defects, congenital, and other congenital anomalies, Atrial septal defect 9, atrioventricular septal defect 5, Persistent truncus arteriosus, Tetralogy of FallotAD1679
GDF1Transposition of the great arteries, dextro-looped 3, Double-outlet right ventricleAD1115
GJA1*Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3AD/AR32106
GJA5Progressive familial heart block, Atrial standstill, digenic, Atrial fibrillationAD/Digenic834
GPC3Simpson-Golabi-Behmel syndromeXL2972
HAND1Congenital heart defects, Dilated cardiomyopathyAD8
HOXA1Athabaskan brainstem dysgenesis syndrome, Bosley-Salih-Alorainy syndromeAR47
HRASCostello syndrome, Congenital myopathy with excess of muscle spindlesAD4129
JAG1Alagille syndromeAD121569
LEFTY2Left-right axis malformationsAD33
MEIS2Cleft palate, cardiac defects, and mental retardation (CPCMR)AD817
MYCNFeingold syndromeAD2540
NAA15Congenital heart malformationsAD68
NF1Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndromeAD8102703
NKX2-5Conotruncal heart malformations, Hypothyroidism, congenital nongoitrous,, Atrial septal defect, Ventricular septal defect 3, Conotruncal heart malformations, variable, Tetralogy of FallotAD43102
NKX2-6Persistent truncus arteriosus, Conotruncal heart malformationsAR29
NODALHeterotaxy, visceralAD413
NOTCH1Aortic valve diseaseAD4491
NOTCH2Alagille syndrome, Hajdu-Cheney syndromeAD3563
NR2F2Congenital heart defects, multiple types, 4AD1014
NSD1Sotos syndrome, Weaver syndrome, Beckwith-Wiedemann syndromeAD303515
PITX2Axenfeld-Rieger syndrome, Ring dermoid of cornea, Iridogoniodysgenesis, Peters anomalyAD2396
PPP1CBNoonan syndrome-like disorder with loose anagen hair 2AD77
PRKD1Congenital heart defects and ectodermal dysplasiaAD26
RBM10TARP syndromeXL1210
SALL4Acro-renal-ocular syndrome, Duane-radial ray/Okohiro syndromeAD1955
SOS2Noonan syndrome 9AD36
TAB2Congenital heart defects, multiple types, 2AD1127
TBX1Conotruncal anomaly face syndromeAD1565
TBX5Holt-Oram syndromeAD55126
TBX20Atrial septal defect 4AD327
TFAP2BPatent ductus arteriosus, nonsyndromic, Char syndromeAD1012
TGDSCatel-Manzke syndromeAR67
TLL1Atrial septal defectAD37
ZFPM246,XY sex reversal, Diaphragmatic hernia 3, Tetralogy of FallotAD944
ZIC3Heterotaxy, visceral, VACTERL association, Congenital heart defects, nonsyndromicXL1441

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number

Panel Update

Genes added

  • ABL1
  • ACTB
  • ACTG1
  • ACVR1
  • ACVR2B
  • ADAMTS10
  • ADAMTS17
  • B3GAT3
  • BCOR
  • CBL
  • CDK13
  • CHD4
  • CRELD1
  • DHCR7
  • EFTUD2
  • EIF2AK4
  • ENG
  • GDF1
  • GPC3
  • HAND1
  • HOXA1
  • LEFTY2
  • MYCN
  • NAA15
  • NKX2-6
  • NR2F2
  • NSD1
  • PITX2
  • PPP1CB
  • PRKD1
  • RBM10
  • SALL4
  • SOS2
  • TAB2
  • TBX20
  • TGDS

Genes removed

  • FOXC1
  • FOXH1
  • G6PC3

Test strength and Limitations

The strengths of this test include:

  • CAP and ISO-15189 accreditations covering all operations at GHC Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in GHC WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: *PPA2* (11, 12). Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:
  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than GHC Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Test Performance

The GHC Genetics panel covers classical genes associated with Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac arrest underlying cardiac condition, cardiac arrest cause unspecified, syncope and collapse, abnormal ECG, Long QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Short QT syndrome. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. GHC Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of GHC Genetics Whole Exome Sequencing (WES) assay.
All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
The performance presented above reached by WES with the following coverage metrics
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Detection of Del/Dup of several genes is by MLPA analysis (MS Holland). All genes are performed by CNV analysis through the genome depending on exon size, sequencing coverage and sequence content. We have validated the assays for different starting materials including isolated DNA from EDTA blood that provide high-quality results.

Bioinformatics & clinical interpretation

The sequencing data generated in our laboratory is analysed by our bioinformatic pipeline, integrating state-of-the art algorithms and industry-standard software solutions. We use also JSI medical systems software for sequencing data analysis. JSI medical systems is a certified system offering sophisticated bioinformatic software solutions covering a wide field of sequencing techniques.

Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results.

Every pathogenic or probably pathogenic variant is confirmed by the Sanger sequencing method. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. The analysis of detected variants was performed on the basis of the reference database of polymorphisms and international mutation databases: UMD, LOVD and ClinVar.

The consequence of variants in coding and splice regions are estimated using Alamut software. The Alamut database contains more than 28000 coding genes, non-protein coding genes and pseudogenes. This database (shared with the high throughput annotation engine for NGS data, Alamut Batch) is frequently updated. Information comes from different public databases such as NCBI, EBI, and UCSC, as well as other sources including gnomAD, ESP, Cosmic, ClinVar, or HGMD and CentoMD (for those a separate subscription from Qiagen/Biobase and Centogene respectively is required). Alamut Visual finds information about nucleotide conservation data through many vertebrates’ species, with the phastCons and phyloP scores, amino acid conservation data through orthologue alignments and information on protein domains.

Moreover, we integrate several missense variant pathogenicity prediction tools and algorithms such as SIFT, PolyPhen, AlignGVGD or MutationTaster. It also offers a window dedicated to the in silico study of variants’ effect on RNA splicing, allowing the assessment of their potential impact on splice junctions and visualization of cryptic or de novo splice sites. Impact on splicing regulation is also assessed.

Clinical interpretation

At GHC Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical report. We recommend an interpretation of the findings of this molecular genetic analysis, including subsequent oncological consultation for the patient in the context of genetic counselling for the patient.

We strive to continuously monitor current genetic literature identifying new relevant information and findings and adapting them to our diagnostics. This enables relevant novel discoveries to be rapidly translated and adopted into our ongoing diagnostics development without delay. The undertaking of such comprehensive due diligence ensures that our diagnostic panels and clinical statements are the most up-to-date on the market.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analysed at our laboratories enables us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant three times at GHC Genetics. Reported variants of uncertain significance (VUS) are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size >10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at GHC Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counselling.

Our Clinical interpretation team analyses millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratories are therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by GHC Genetics is re-classified, our laboratories will issue a follow-up statement to the original ordering health care provider at no additional cost.