What genetic biomarkers are associated with Interstitial Lung Disease (ILD)?

Genetic Biomarkers for Interstitial Lung Disease

The key genetic biomarkers associated with ILD include telomerase complex genes (TERT and TERC), surfactant protein genes (SFTPC and SFTPA2), and the MUC5B promoter variant, with these mutations accounting for approximately 20% of familial interstitial pneumonias and conferring significant risk for both familial and sporadic disease. 1

Primary Genetic Mutations in Familial ILD

The most clinically relevant genetic biomarkers are:

• TERT mutations occur in approximately 15% of familial interstitial pneumonias and represent the most common identified genetic cause 1
• TERC mutations account for approximately 1% of familial cases 1
• SFTPC mutations are found in approximately 1% of familial ILD cases 1
• SFTPA2 mutations similarly account for approximately 1% of cases 1

These four genes collectively explain about 20% of all familial interstitial pneumonias, meaning 80% of familial cases remain genetically unexplained despite evidence of autosomal dominant inheritance patterns 1

MUC5B Promoter Variant

• The MUC5B promoter variant is a common genetic polymorphism strongly associated with both familial and sporadic IPF 1
• This variant increases risk for interstitial lung abnormalities (ILAs) in asymptomatic first-degree relatives of IPF patients 1
• A polygenic risk score incorporating the MUC5B promoter variant and other common IPF risk variants demonstrates substantial predictive power for presence and progression of ILAs 1

Clinical Manifestations Suggesting Genetic Causes

When evaluating patients for potential genetic ILD, systematically search for these clinical features associated with telomerase complex mutations (dyskeratosis congenita phenotype): 1

• Macrocytosis on complete blood count
• Refractory anemia due to erythroblastopenia
• Cryptogenic hepatic cirrhosis
• Abnormal cutaneous pigmentation
• Mucosal abnormalities including leukoplakia of the tongue margin
• Leukotrichia (premature greying of hair)

Who Should Undergo Genetic Testing

Genetic testing should be prioritized for: 1

• Patients presenting with IPF at age <50 years, as younger age increases probability of genetic cause 1
• Any patient with a family history of ILD in first-degree relatives (parent, child, sibling) 1
• Patients with clinical or laboratory features suggesting dyskeratosis congenita 1
• First-degree relatives of patients with familial pulmonary fibrosis, especially those >50 years of age with smoking history 1

Familial ILD Patterns

• Familial forms affect <5% of IPF patients but may represent 2-20% of all idiopathic interstitial pneumonias depending on the cohort studied 1
• Most familial cases (80%) demonstrate autosomal dominant inheritance with variable penetrance 1
• Between 15-30% of asymptomatic first-degree relatives of IPF patients have interstitial lung abnormalities on chest CT, associated with older age, smoking, MUC5B variant, and reduced telomere length 1

Telomere Biology in Sporadic Disease

• Sporadic IPF without telomerase mutations is often associated with telomere shortening, suggesting pathways involved in familial disease contribute to sporadic cases 1
• This finding bridges the gap between familial and sporadic disease mechanisms 1

Recommended Genetic Testing Approach

For patients with suspected familial ILD or young-onset disease: 1

• Refer to specialized genetics outpatient clinic to establish detailed pedigree
• Prioritize molecular genetic analysis targeting telomerase complex genes (TERT and TERC) first
• Include surfactant protein-C gene (SFTPC) testing
• Consider SFTPA2 and MUC5B promoter variant testing based on clinical context

Clinical Utility and Limitations

The current evidence reveals important gaps:

• Despite known genetic associations, 80% of familial ILD cases have no identifiable mutation with current testing 1
• Familial IIPs can be radiologically and histologically indistinguishable from sporadic cases 1
• All patients with suspected idiopathic interstitial pneumonia should be questioned about family history, as this guides genetic testing decisions and evaluation of other family members 1

Emerging Evidence on Testing Perceptions

Recent survey data indicates strong support for genetic testing implementation, with 72% of pulmonologists potentially changing diagnostic work-up and 57% potentially changing therapeutic approach following genetic testing results 2. However, limited access to genetic tests remains a barrier, with one-third of pulmonologists who would offer testing currently unable to do so 2.