Comprehensive Pulmonology Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: PU0701

The Blueprint Genetics Comprehensive Pulmonology Panel is a 61 gene test for genetic diagnostics of patients with clinical suspicion of inherited pulmonary disease.

This panel covers nonsyndromic disorders as well as a number of syndromes, where pulmonary symptoms occur with systemic diseases. The main phenotypes are cystic fibrosis, primary ciliary dyskinesia, alpha-1-antitrypsin deficiency and interstitial lung diseases. Inheritance pattern is usually autosomal dominant or autosomal recessive. Pulmonary diseases are genetically highly heterogeneous with significant phenotypic overlap. Genetic diagnostics is used to determine definitive diagnoses and to enable individualized treatment and management decisions. The Comprehensive Pulmonology Panel is recommended for clinically complex cases where the diagnosis is not clear. This panel includes the following subpanels under the Pulmonology category: Bronchiectasis Panel, Central Hypoventilation and Apnea Panel, Cystic Fibrosis Panel, Cystic Lung Disease Panel, Interstitial Lung Disease Panel, Neonatal Respiratory Distress – Surfactant Dysfunction Panel.

About pulmonary diseases

Inherited pulmonary diseases are a group of lung disorders with variable clinical presentation. The diseases can affect the airways (e.g. cystic fibrosis and primary ciliary dyskinesia), parenchyma (pulmonary fibrosis, Birt Hogg Dube syndrome and tuberous sclerosis) and vasculature of the lung. Rare lung diseases generally affect individuals from birth through about age 60. They are in many cases serious, chronic, and devastating, and once properly diagnosed, often require expensive, long-term treatments. The most common genetic respiratory disease is cystic fibrosis. Misdiagnosis can lead to inappropriate care and increased risk of severe complications. Genetic diagnostics by NGS offers a fast approach to correct clinical diagnosis and early intervention.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Comprehensive Pulmonology Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ABCA3 Interstitial lung disease, Surfactant metabolism dysfunction, pulmonary AD/AR 11 181
CCDC39 Ciliary dyskinesia AR 13 38
CCDC40 Ciliary dyskinesia AR 15 31
CFTR Cystic fibrosis AR 366 1767
CHAT Myasthenic syndrome, congenital AR 14 68
CHRNA1 Myasthenic syndrome, congenital AD/AR 19 32
CHRNB1 Myasthenic syndrome AD/AR 5 8
CHRND Myasthenic syndrome AD/AR 12 19
CHRNE Myasthenic syndrome AD/AR 26 121
COLQ Myasthenic syndrome, congenital AR 12 66
CSF2RA* Surfactant metabolism dysfunction, pulmonary XL 2 14
DKC1 Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenita XL 45 69
DNAAF1 Ciliary dyskinesia AR 8 28
DNAAF2 Ciliary dyskinesia AR 4 3
DNAH5 Ciliary dyskinesia AR 36 135
DNAH11* Ciliary dyskinesia AR 25 90
DNAI1 Ciliary dyskinesia AR 10 28
DNAI2 Ciliary dyskinesia AR 7 6
DNAL1 Ciliary dyskinesia AR 3 1
EDN3 Hirschsprung disease, Central hypoventilation syndrome, congenital, Waardenburg syndrome AD/AR 6 21
EFEMP2 Cutis laxa AR 11 15
ELMOD2 Familial idiopathic pulmonary fibrosis AD/AR
ELN Cutis laxa, Supravalvular aortic stenosis AD 67 104
FBLN5 Cutis laxa, Macular degeneration, age-related AD/AR 13 21
FLCN Birt-Hogg-Dube syndrome, Pneumothorax, primary spontaneous AD 85 165
FOXF1 Alveolar capillary dysplasia with misalignment of pulmonary veins AD 7 95
GLRA1 Hyperekplexia AD/AR 26 67
HPS1* Hermansky-Pudlak syndrome AR 26 41
HPS4 Hermansky-Pudlak syndrome AR 14 15
ITGA3 Interstitial lung disease with nephrotic syndrome and epidermolysis bullosa AR 6 11
LTBP4 Cutis laxa with severe pulmonary, gastrointestinal, and urinary abnormalities AR 9 16
MECP2 Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardation XL 429 937
NF1* Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndrome AD 261 2607
NKX2-1 Thyroid cancer, nonmedullary, Choreoathetosis, hypothyroidism, and neonatal respiratory distress AD 13 123
NME8 Ciliary dyskinesia AR 1 6
PARN* Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenita AD/AR 11 19
PHOX2B Central hypoventilation syndrome, congenital, Neuroblastoma, susceptiblity to, Neuroblastoma with Hirschsprung disease AD 5 70
RAPSN Myasthenic syndrome, congenital AR 18 57
RET Hirschsprung disease, Central hypoventilation syndrome, congenital, Pheochromocytoma, Medullary thyroid carcinoma, Multiple endocrine neoplasia AD/AR 80 405
RSPH4A Ciliary dyskinesia AR 7 21
RSPH9 Ciliary dyskinesia AR 2 11
RTEL1 Pulmonary fibrosis and/or bone marrow failure, Dyskeratosis congenita AD/AR 27 26
SCN4A Hyperkalemic periodic paralysis, Myotonia, potassium-aggravated, Paramyotonia congenita, Myasthenic syndrome, congenital, Normokalemic potassium-sensitive periodic paralysis AD/AR 45 101
SCNN1A Pseudohypoaldosteronism, Bronchiectasis with or without elevated sweat chloride AR/Digenic (with CFTR or other SCCN1 genes) 7 44
SCNN1B Liddle syndrome, Pseudohypoaldosteronism, Bronchiectasis with or without elevated sweat chloride AD/AR 13 44
SERPINA1 Alpha-1-antitrypsin deficiency AR 29 82
SFTPA1 Idiopathic pulmonary fibrosis AD 5
SFTPA2 Pulmonary fibrosis, idiopathic AD 2 8
SFTPB Surfactant metabolism dysfunction, pulmonary AR 5 30
SFTPC Surfactant metabolism dysfunction, pulmonary AD 7 81
SLC6A5 Hyperekplexia AR 10 32
SLC7A7 Lysinuric protein intolerance AR 51 65
SLC34A2 Pulmonary alveolar microlithiasis AR 5 18
SMPD1 Niemann-Pick disease AR 52 230
STAT3 Hyper-IgE recurrent infection syndrome, Autoimmune disease, multisystem, infantile onset AD 27 133
TERC Aplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenita AD 36 60
TERT Aplastic anemia, Pulmonary fibrosis and/or bone marrow failure, telomere-related, Dyskeratosis congenita AD/AR 39 133
TINF2 Revesz syndrome, Dyskeratosis congenita AD 20 33
TSC1 Lymphangioleiomyomatosis, Tuberous sclerosis AD 61 306
TSC2 Lymphangioleiomyomatosis, Tuberous sclerosis AD 141 977
ZEB2* Mowat-Wilson syndrome AD 104 247

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
CFTR Chr7:117229530 c.1680-877G>T NM_000492.3 rs397508261
CFTR Chr7:117251609 c.3140-26A>G NM_000492.3 rs76151804
CFTR Chr7:117280015 c.3718-2477C>T NM_000492.3 rs75039782
CHRNE Chr17:4806454 c.-96C>T NM_000080.3 rs748144899
DKC1 ChrX:153991099 c.-142C>G NM_001363.3 rs199422241
NF1 Chr17:29577934 c.4110+1802delA NM_001042492.2 rs863224944
NF1 Chr17:29657848 c.5812+332A>G NM_001042492.2 rs863224491
RAPSN Chr11:47470715 c.-199C>G NM_005055.4
RAPSN Chr11:47470726 c.-210A>G NM_005055.4 rs786200905
TSC2 Chr16:2098067 c.-30+1G>C NM_000548.3 rs587778004

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

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
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

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.

Blueprint Genetics offers a Comprehensive Pulmonology Panel that covers classical genes associated with inherited pulmonary disease. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

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. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint 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 statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. 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. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • 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.

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