- Is a 62 gene panel that includes assessment of non-coding variants
Is 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.
The Blueprint Genetics Congenital Structural Heart Disease Panel (test code CA1501):
Commonly used ICD-10 code(s) when ordering the Congenital Structural Heart Disease Panel
|Q21.3||Tetralogy of Fallot|
|Q25.3||Supravalvular aortic stenosis|
- Blood (min. 1ml) in an EDTA tube
- Extracted DNA, min. 2 μg in TE buffer or equivalent
- Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)
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. Read more about our sample requirements here.
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.
Genes in the Congenital Structural Heart Disease Panel and their clinical significance
|ABL1||Congenital heart defects and skeletal malformations syndrome (CHDSKM)||AD||30||5|
|ACTA2||Aortic aneurysm, familial thoracic, Moyamoya disease, Multisystemic smooth muscle dysfunction syndrome||AD||20||76|
|ACTC1||Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Atrial septal defect, Dilated cardiomyopathy (DCM)||AD||23||63|
|ACTG1*||Deafness, Baraitser-Winter syndrome||AD||27||47|
|ACVR1||Fibrodysplasia ossificans progressiva||AD||14||19|
|ACVR2B||Heterotaxy, visceral, 4, autosomal||AD||1||2|
|B3GAT3*||Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects||AR||6||13|
|BCOR||Microphthalmia, syndromic, Oculofaciocardiodental syndrome||XL||40||53|
|BMPR2||Pulmonary hypertension, primary, Pulmonary venoocclusive disease||AD||391||572|
|CBL||Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia||AD||24||43|
|CDK13||Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder||AD||13||20|
|CHD7||Isolated gonadotropin-releasing hormone deficiency, CHARGE syndrome||AD||276||860|
|CRELD1||Atrioventricular septal defect, partial, with or without heterotaxy||AD||2||16|
|CTC1||Cerebroretinal microangiopathy with calcifications and cysts||AR||21||33|
|EFTUD2||Mandibulofacial dysostosis with microcephaly, Esophageal atresia, syndromic||AD||45||99|
|EIF2AK4||Pulmonary venoocclusive disease||AR||27||84|
|ELN||Cutis laxa, Supravalvular aortic stenosis||AD||78||113|
|ENG||Juvenile polyposis syndrome, Hereditary hemorrhagic telangiectasia||AD||158||491|
|FLNA||Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects||XL||133||257|
|GATA4||Tetralogy of Fallot, Atrioventricular septal defect, Testicular anomalies with or without congenital heart disease, Ventricular septal defect, Atrial septal defect||AD||37||140|
|GATA5||Familial atrial fibrillation, Tetralogy of Fallot, Single ventricular septal defect||AD||5||32|
|GATA6||Heart defects, congenital, and other congenital anomalies, Atrial septal defect 9, atrioventricular septal defect 5, Persistent truncus arteriosus, Tetralogy of Fallot||AD||16||82|
|GDF1||Transposition of the great arteries, dextro-looped 3, Double-outlet right ventricle||AD||11||15|
|GJA1*||Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3||AD/AR||31||107|
|GJA5||Progressive familial heart block, Atrial standstill, digenic, Atrial fibrillation||AD/Digenic||8||34|
|HAND1||Congenital heart defects, Dilated cardiomyopathy||AD||9|
|HOXA1||Athabaskan brainstem dysgenesis syndrome, Bosley-Salih-Alorainy syndrome||AR||4||7|
|HRAS||Costello syndrome, Congenital myopathy with excess of muscle spindles||AD||43||31|
|LEFTY2*||Left-right axis malformations||AD||1||3|
|MEIS2||Cleft palate, cardiac defects, and mental retardation (CPCMR)||AD||10||18|
|NAA15||Congenital heart malformations||AD||10||32|
|NF1*||Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndrome||AD||1157||2901|
|NKX2-5||Conotruncal heart malformations, Hypothyroidism, congenital nongoitrous,, Atrial septal defect, Ventricular septal defect 3, Conotruncal heart malformations, variable, Tetralogy of Fallot||AD||45||108|
|NKX2-6||Persistent truncus arteriosus, Conotruncal heart malformations||AD/AR||2||9|
|NOTCH1||Aortic valve disease||AD||56||96|
|NOTCH2*||Alagille syndrome, Hajdu-Cheney syndrome||AD||37||70|
|NR2F2||Congenital heart defects, multiple types, 4||AD||12||16|
|NSD1||Sotos syndrome, Weaver syndrome, Beckwith-Wiedemann syndrome||AD||329||517|
|PITX2||Axenfeld-Rieger syndrome, Ring dermoid of cornea, Iridogoniodysgenesis, Peters anomaly||AD||23||101|
|PPP1CB#||Noonan syndrome-like disorder with loose anagen hair 2||AD||8||11|
|PRKD1||Congenital heart defects and ectodermal dysplasia||AD||2||7|
|SALL4||Acro-renal-ocular syndrome, Duane-radial ray/Okohiro syndrome||AD||21||56|
|SOS2||Noonan syndrome 9||AD||4||6|
|TAB2||Congenital heart defects, multiple types, 2||AD||13||31|
|TBX1||Conotruncal anomaly face syndrome||AD||17||72|
|TBX20*||Atrial septal defect 4||AD||4||28|
|TFAP2B||Patent ductus arteriosus, nonsyndromic, Char syndrome||AD||10||12|
|TLL1||Atrial septal defect||AD||3||7|
|ZFPM2||46,XY sex reversal, Diaphragmatic hernia 3, Tetralogy of Fallot||AD/AR||9||50|
|ZIC3||Heterotaxy, visceral, VACTERL association, Congenital heart defects, nonsyndromic||XL||15||41|
* Some, or all, of the gene is duplicated in the genome. Read more.
# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).
The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)
Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.
Non-coding variants covered by Congenital Structural Heart Disease Panel
|Gene||Genomic location HG19||HGVS||RefSeq||RS-number|
- CAP and ISO-15189 accreditations covering all operations at Blueprint 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 Blueprint 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
Genes with suboptimal coverage in our assay are marked with number sign (#) and 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. Gene is considered to have suboptimal coverage when >90% of the gene’s target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).
- 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).
- Low level mosaicism (variant with a minor allele fraction of 14.6% is detected with 90% probability)
- 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 Blueprint Genetics.
For additional information, please refer to the Test performance section and see our Analytic Validation.
The Blueprint Genetics congenital structural heart disease panel covers classical genes associated with tetralogy of Fallot, Holt-Oram syndrome, supravalvular aortic stenosis, Alagille syndrome, atrial septal defect, ventricular septal defect, aorta stenosis, ebstein anomaly, Hypoplastic left heart syndrome and pulmonary artery stenosis. 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. Blueprint 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 Blueprint 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%|
The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.
We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.
Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. 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 analyzed at our laboratory allowed us to further develop the industry standard.
The final step in the analysis is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance
(VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a 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 Blueprint Genetics (Plus analysis only).
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, congress abstracts 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 counseling.
Our interpretation team analyzes 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 laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.