Interstitial Lung Disease Panel

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).

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

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).

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.

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

This panel typically provides 98.9% 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).

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.

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).