Inherited Causes of Pulmonary Fibrosis
The main inherited causes of pulmonary fibrosis are mutations in genes related to telomere maintenance and surfactant metabolism, with telomere-related gene mutations being significantly more common. 1
Telomere-Related Gene Mutations
Telomere-related gene mutations represent the most common genetic cause of familial pulmonary fibrosis (FPF) and are associated with a syndrome called telomeropathy, which can manifest with multiple clinical features:
- Telomere length maintenance genes: TERT and TERC mutations are the most frequently identified genetic causes of FPF 1
- Telomerase complex formation genes: PARN, DKC1, NAF1, ZCCHC8, and NOP10 1
- Telomere structure genes: RTEL1 (unwinding telomere structure during DNA replication) and TINF2 (maintaining integrity of telomere ends) 1, 2
These mutations typically follow an autosomal dominant inheritance pattern with variable penetrance, except for DKC1, which causes X-linked inheritance 1. Patients with telomere-related mutations often display extrapulmonary manifestations including:
Surfactant-Related Gene Mutations
Surfactant gene mutations account for approximately 1-3% of familial pulmonary fibrosis cases 1. These mutations affect the following genes:
- Surfactant protein C (SFTPC): Heterozygous variants causing variable pulmonary fibrosis phenotypes from neonates to elderly adults 1
- Surfactant protein A (SFTPA1, SFTPA2): Associated with both familial pulmonary fibrosis and lung adenocarcinoma in some families 1
- Surfactant protein B (SFTPB): More commonly associated with neonatal respiratory distress syndrome and pediatric interstitial lung disease 1
- ATP-binding cassette-type 3 (ABCA3): Homozygous loss-of-function variants cause respiratory failure at birth, while compound heterozygous variants result in variable presentation 1, 4
- NKX2-1 (transcription factor): Associated with brain and thyroid disease in addition to pulmonary fibrosis 1
Syndromic Presentations
Several genetic syndromes include pulmonary fibrosis as a manifestation:
Dyskeratosis congenita (DC): A telomere syndrome characterized by dysplastic nails, lacy reticular skin pigmentation, and oral leukoplakia. Pulmonary fibrosis may manifest in late adolescence or early adulthood. Mutations in at least 11 genes have been implicated (ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53) 1
Hermansky-Pudlak syndrome (HPS): Characterized by oculocutaneous albinism and bleeding diathesis. Pulmonary fibrosis often manifests in the third decade of life. Associated genes include AP3B1, HPS1, HPS3, HPS4, HPS5, HPS6, and less commonly AP3D1, BLOC1S3, BLOC1S6, and DTNBP1 1
Clinical Implications and Management
Genetic testing should be considered in patients with familial pulmonary fibrosis or those with features suggestive of telomere syndromes or other genetic disorders 1
Patients with telomere-related gene mutations have a worse prognosis with a median time to death or transplant of approximately 2.87 years 3
The presence of a disease-causing variant in an affected family member has implications for relatives, who should be offered genetic counseling 1
Genetic anticipation can occur in families with telomere gene mutations, resulting in earlier age of onset and more severe disease in subsequent generations 1
Important Clinical Considerations
Age at presentation varies by gene mutation - patients with TERC mutations are typically diagnosed at an earlier age than those with PARN mutations 3
Laboratory findings that may suggest telomere-related mutations include red blood cell macrocytosis and low platelet count 5
Despite different genetic causes, the clinical course of telomere-related pulmonary fibrosis is uniformly progressive regardless of the specific interstitial lung disease diagnosis 3
Lung transplantation should be considered early in the disease course for patients with genetic forms of pulmonary fibrosis due to their rapid progression 2