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Interstitial Lung Disease Sequencing Panel

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
5211 ABCA3 81479 Add to Order
CFTR 81223
CSF2RB 81479
DKC1 81479
FLCN 81479
HPS1 81479
HPS4 81479
ITGA3 81479
NF1 81408
NKX2-1 81479
PARN 81479
RTEL1 81479
SFTPA2 81479
SFTPB 81479
SFTPC 81479
SLC34A2 81479
SLC7A7 81479
SMPD1 81479
STAT3 81479
TERC 81479
TERT 81479
TINF2 81479
TSC1 81406
TSC2 81407
Full Panel Price* $1770.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
5211 Genes x (24) $1770.00 81223, 81406, 81407, 81408, 81479(x20) Add to Order
Pricing Comment

If you would like to order a subset of these genes contact us to discuss pricing.

Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

This multi-gene panel analyzes 24 genes associated with disorders that primarily affect the lung as well as systemic disorders affecting multiple organs. The clinical sensitivity for this test is hard to predict at this time, but it should detect causative variants in ~15-20% of familial pulmonary fibrosis patients (Diaz de Leon et al. 2011; Garcia et al. 2011; van Moorsel et al. 2010).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 ABCA3$690.00 81479 Add to Order
CFTR$690.00 81222
DKC1$690.00 81479
FLCN$690.00 81479
HPS1$690.00 81479
HPS4$690.00 81479
ITGA3$690.00 81479
NF1$540.00 81479
NKX2-1$690.00 81479
SFTPB$690.00 81479
SFTPC$690.00 81479
SMPD1$690.00 81479
STAT3$690.00 81479
TERT$690.00 81479
TINF2$690.00 81479
TSC1$540.00 81405
TSC2$540.00 81406
Full Panel Price* $1290.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
600 Genes x (17) $1290.00 81222, 81405, 81406, 81479(x14) Add to Order
Pricing Comment

NF1, TSC1, and TSC2 are analyzed by Multiplex Ligation-dependent Probe Amplification.

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Gross deletions or duplications have been reported in ABCA3, DKC1, FLCN, NF1,NKX2-1, PARN, SFTPB, SFTPC,SLC7A7, SLC34A2 TERC,TERT, TSC1, and TSC2 (Human Gene Mutation Database). Overall clinical sensitivity is difficult to predict due to the paucity of documented cases, but is expected to be low.

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Clinical Features

Interstitial lung diseases (ILDs), or diffuse parenchymal lung diseases, are a heterogeneous group of disorders that affect the tissue and spaces between the air sacs of the lungs (the interstitium). They include over 200 different pulmonary disorders (Schraufnagel 2010). ILDs can be associated with disorders that primarily affect the lung as well as systemic disorders affecting multiple organs. Many of the ILDs cause thickening of the interstitium due to inflammation, scarring (fibrosis), or edema, thus leading to irreversible architectural distortion and impaired gas exchange. The most common ILD is idiopathic pulmonary fibrosis (IPF) that can cluster in families and often defined as familial pulmonary fibrosis. Patients affected by ILD usually present with shortness of breath which may get worse over time. Other symptoms include dry cough and weight loss (Devine et al. 2012).

Genetics

Idiopathic pulmonary fibrosis (IPF), the most common interstitial lung disease (ILD), has been associated with pathogenic variants in genes encoding telomerases (TERT, TERC). These pathogenic variants lead to telomerase dysfunction, impaired maintenance of telomeres, and reduced telomere length. Surfactant protein-associated genes SFTPC, SFTPA2, ABCA3 and CSF2RB are also found in cases with idiopathic pulmonary fibrosis. Autosomal dominant pathogenic variants in four genes (TERT, TERC, SFTPC, and SFTPA2) are known to count for ~15% of cases with familial pulmonary fibrosis (Talbert et al. 2015). Moreover, this panel contains a substantial set of other genes associated with syndromes that may also present with interstitial lung disease (Devine et al. 2012). The FLCN, NF1, NKX2-1, PARN, SFTPA2, SFTPC, TERC, TINF2, TSC1, TSC2 and STAT3 genes are associated with autosomal dominant pulmonary disorders. The ABCA3, CFTR, CSF2RB, HPS1, HPS4, ITGA3, SFTPB, SLC7A7, SLC34A2, and SMPD1 genes are associated with autosomal recessive disorders. The DKC1 gene is associated with X-linked recessive disorders. The TERT and RTEL1 gene are associated with both autosomal dominant or recessive disorders. See individual gene test descriptions for information on molecular biology of gene products.

Phenotypes covered by this panel include:

Dyskeratosis congenita: DKC1, TERC, TERT, TINF2, RTEL1

Familial Pulmonary Fibrosis: TERT, TERC, SFTPA2, RTEL1, PARN

Neurofibromatosis, type I: NF1

Tuberous Sclerosis: TSC1, TSC2

Birt-Hogg-Dubé Syndrome: FLCN

Hyper IgE syndrome: STAT3

Cystic Fibrosis: CFTR

Hermansky-Pudlak syndrome: HPS1, HPS4

Niemann-Pick disease, type B: SMPD1

Lysinuric Protein Intolerance: SLC7A7

Surfactant metabolism dysfunction: SFTPB, SFTPC, ABCA3, CSF2RB

Pulmonary Alveolar Microlithiasis: SLC34A2, ITGA3

Congenital Interstitial lung disease with Nephrotic syndrome and Epidermolysis Bullosa: ITGA3

Choreoathetosis, hypothyroidism, and neonatal respiratory distress: NKX2-1

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for regions not captured or with insufficient number of sequence reads. All reported pathogenic, likely pathogenic, and variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

This panel provides at least 98.15% coverage of all coding exons of the genes listed, plus ~20 bases of flanking noncoding DNA. We define coverage as >20X NGS reads for coding regions and 0-10 bases of flanking DNA, >10X NGS reads for 11-20 bases of flanking DNA, or Sanger sequencing.

Genes without complete coverage: CFTR, DKC1, NF1, SLC34A2, SMPD1, TERT, and TSC2. A full list of regions not covered by NGS or Sanger sequencing is available upon request.

Indications for Test

This test is recommended for individuals with clinical suspicion of familial idiopathic pulmonary fibrosis or other interstitial pulmonary diseases.

Genes

Official Gene Symbol OMIM ID
ABCA3 601615
CFTR 602421
CSF2RB 138981
DKC1 300126
FLCN 607273
HPS1 604982
HPS4 606682
ITGA3 605025
NF1 613113
NKX2-1 600635
PARN 604212
RTEL1 608833
SFTPA2 178642
SFTPB 178640
SFTPC 178620
SLC34A2 604217
SLC7A7 603593
SMPD1 607608
STAT3 102582
TERC 602322
TERT 187270
TINF2 604319
TSC1 605284
TSC2 191092
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Birt-Hogg-Dube Syndrome AD 135150
Choreoathetosis, Hypothyroidism, And Neonatal Respiratory Distress AD 610978
Cystic Fibrosis AR 219700
Dyskeratosis Congenita Autosomal Dominant AD 127550
Dyskeratosis Congenita X-Linked XL 305000
Dyskeratosis Congenita, Autosomal Dominant 4 AD 615190
Dyskeratosis Congenita, Autosomal Dominant, 2 AD, AR 613989
Dyskeratosis Congenita, Autosomal Dominant, 3 AD 613990
Dyskeratosis Congenita, Autosomal Recessive 6 AR 616353
Hermansky-Pudlak Syndrome 1 AR 203300
Hermansky-Pudlak Syndrome 4 AR 614073
Hyperimmunoglobulin E Syndrome AD 147060
Idiopathic Fibrosing Alveolitis, Chronic Form AD 178500
Interstitial Lung Disease, Nephrotic Syndrome, and Epidermolysis Bullosa, Congenital AR 614748
Lysinuric Protein Intolerance AR 222700
Neurofibromatosis, Type 1 AD 162200
Niemann-Pick Disease, Type B AR 607616
Pulmonary Alveolar Microlithiasis AR 265100
Pulmonary Fibrosis and/or Bone Marrow Failure, Telomere-Related, 3 AD 616373
Pulmonary Fibrosis and/or Bone Marrow Failure, Telomere-Related, 4 AD 616371
Surfactant Metabolism Dysfunction, Pulmonary, 1 AR 265120
Surfactant Metabolism Dysfunction, Pulmonary, 2 AD 610913
Surfactant Metabolism Dysfunction, Pulmonary, 3 AR 610921
Surfactant Metabolism Dysfunction, Pulmonary, 5 AR 614370
Tuberous Sclerosis 1 AD 191100
Tuberous Sclerosis 2 AD 613254

Related Tests

Name
Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Panel
Autosomal Dominant Hyper IgE Syndrome via the STAT3 Gene
Birt-Hogg-Dube Syndrome via the FLCN Gene
Bleeding Disorders Sequencing Panel
Cancer Sequencing and Deletion/Duplication Panel
Chronic Pancreatitis Sequencing Panel
Ciliopathy Sequencing Panel
Congenital Hypothyroidism (Thyroid Dysgenesis) via the NKX2-1/TTF1 Gene
Congenital Hypothyroidism and Thyroid Hormone Resistance Sequencing Panel
Congenital Interstitial Lung Disease with Nephrotic Syndrome and Epidermolysis Bullosa (ILNEB) via the ITGA3 Gene
Cystic Fibrosis and CF-Related Disorders via the CFTR Gene
Disorders of Sex Development and Infertility Sequencing Panel
Dyskeratosis Congenita (DC) and Hoyeraal-Hreidarsson Syndrome via the DKC1 Gene
Dyskeratosis Congenita (DC) and Related Disorders Sequencing Panel
Dyskeratosis Congenita (DC) and Revesz Syndrome via the TINF2 Gene
Dyskeratosis Congenita (DC) via the TERT Gene
Hereditary Myelodysplastic Syndrome (MDS) / Acute Myeloid Leukemia (AML) Sequencing Panel
Hereditary Paraganglioma-Pheochromocytoma Syndrome Sequencing Panel
Hermansky-Pudlak Syndrome (HPS) Sequencing Panel
Hermansky-Pudlak Syndrome Type 1 (HPS1) via the HPS1 Gene
Hermansky-Pudlak Syndrome Type 4 (HPS4) via the HPS4 Gene
Hyperammonemia Sequencing Panel
Male Infertility Sequencing Panel
Nephrotic Syndrome (NS)/Focal Segmental Glomerulosclerosis (FSGS) Sequencing Panel
Neurofibromatosis Type 1 and Legius Syndrome Sequencing Panel
Neurofibromatosis Type 1 and Related Disorders via the NF1 Gene
Neurofibromatosis Type 1 and Related Disorders via the NF1 Gene
Niemann-Pick Disease Types A and B via the SMPD1 Gene
Platelet Function Disorder Sequencing Panel
Primary Ciliary Dyskinesia (PCD)/Immotile Cilia Syndrome and Cystic Fibrosis Sequencing Panel
Pulmonary Fibrosis and Surfactant Dysfunction Disorders Sequencing Panel
Pulmonary Fibrosis Syndrome via the SFTPA2 Gene
Renal Cancer Sequencing Panel
Surfactant Protein B Deficiency via the SFTPB Gene
Surfactant Protein C Deficiency via the SFTPC gene
Tuberous Sclerosis Complex Sequencing and Deletion/Duplication Panel
Tuberous Sclerosis Complex via the TSC1 Gene
Tuberous Sclerosis Complex via the TSC1 Gene
Tuberous Sclerosis Complex via the TSC2 Gene
Tuberous Sclerosis Complex via the TSC2 Gene
X-Linked Intellectual Disability Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Devine M.S., Garcia C.K. 2012. Clinics in Chest Medicine. 33: 95-110. PubMed ID: 22365249
  • Diaz de Leon A. et al. 2011. Chest. 140: 753-763. PubMed ID: 21349926
  • Garcia C.K. 2011. Proceedings of the American Thoracic Society. 8: 158-62. PubMed ID: 21543794
  • Human Gene Mutation Database (Bio-base).
  • Schraufnagel D. 2010. American Thoracic Society.
  • Talbert J.L.. et al. 2015. Pulmonary Fibrosis, Familial. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301408
  • van Moorsel C.H. et al. 2010. American Journal of Respiratory and Critical Care Medicine. 182: 1419-25. PubMed ID: 20656946
Order Kits
TEST METHODS

Exome Sequencing with CNV Detection

Test Procedure

For the PGxome we use Next Generation Sequencing (NGS) technologies to cover the coding regions of targeted genes plus ~10 bases of non-coding DNA flanking each exon. As required, genomic DNA is extracted from patient specimens. Patient DNA corresponding to these regions is captured using Agilent Clinical Research Exome hybridization probes. Captured DNA is sequenced on the NovaSeq 6000 using 2x150 bp paired-end reads (Illumina, San Diego, CA, USA). The following quality control metrics are generally achieved: >97% of target bases are covered at >20x, and mean coverage of target bases >120x. Data analysis and interpretation is performed by the internally developed software Titanium-Exome. In brief, the output data from the NovaSeq 6000 is converted to fastqs by Illumina Bcl2Fastq, and mapped by BWA. Variant calls are made by the GATK Haplotype caller and annotated using in house software and SnpEff. Variants are filtered and annotated using VarSeq (www.goldenhelix.com). Common benign, likely benign, and low quality variants are filtered from analysis. All reported pathogenic, likely pathogenic, and variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

Analytical Validity
Analytical Limitations

Interpretation of the test results is limited by the information that is currently available. Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

Sequencing: When sequencing does not reveal any heterozygous differences from the reference sequence, we cannot be certain that we were able to detect both patient alleles.

For technical reasons, the PGxome test is not 100% sensitive. Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies in the genome. Therefore, a small fraction of sequence variants relevant to the patient's health will not be detected.

We sequence coding exons for most given transcripts, plus ~10 bp of flanking non-coding DNA for each exon. Unless specifically indicated, test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions, uncharacterized alternative exons, chromosomal rearrangements, repeat expansions, epigenetic effects, and mitochondrial genome variants.

In most cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient's nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during amplification.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes if taken from whole blood). Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Copy Number Variant Analysis: The PGxome test detects most deletions and duplications including intragenic CNVs and large cytogenetic events; however aberrations in a small percentage of regions may not be accurately detected due to sequence paralogy (e.g., pseudogenes, segmental duplications), sequence properties, deletion/duplication size (e.g., 1-3 exons vs. 4 or more exons), and inadequate coverage. In general, sensitivity for single, double, or triple exon CNVs is ~70% and for CNVs of four exon size or larger is >95%, but may vary from gene-to-gene based on exon size, depth of coverage, and characteristics of the region.

Balanced translocations or inversions are only rarely detected.

Certain types of sex chromosome aneuploidy may not be detected.  

In nearly all cases, our ability to determine the exact copy number change within a targeted region is limited.

Our ability to detect CNVs due to somatic mosaicism is limited.

The sensitivity of this test is dependent on DNA quality.

General: We have confidence in our ability to track a specimen once it has been received by PreventionGenetics. However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

A negative finding does not rule out a genetic diagnosis.

Genetic counseling to help to explain test results to the patients and to discuss reproductive options is recommended.

Deletion/Duplication Testing Via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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