Should I order RTEL1 genetic testing for a patient with early‑onset pulmonary fibrosis, a family history of similar lung disease and signs of telomere shortening such as premature greying, nail dystrophy, or bone‑marrow failure, and what management is recommended if a pathogenic variant is identified?

RTEL1 Genetic Testing in Early-Onset Pulmonary Fibrosis with Telomeropathy Features

Yes, you should order RTEL1 genetic testing for this patient, as the combination of early-onset pulmonary fibrosis, family history, and telomeropathy signs (premature greying, nail dystrophy, bone marrow failure) creates a high pretest probability for pathogenic telomere gene variants, with RTEL1 accounting for 2-5% of familial pulmonary fibrosis cases. 1

Clinical Rationale for Testing

Your patient's presentation strongly suggests a telomeropathy syndrome. RTEL1 is a DNA helicase responsible for unwinding telomere structure during DNA replication, and pathogenic variants cause telomere dysfunction leading to the multisystem manifestations you're observing. 1

Key Diagnostic Features Present

• Early-onset pulmonary fibrosis (age <50 years) is a cardinal feature of telomere pathway disorders 1
• Family history of similar lung disease indicates familial pulmonary fibrosis, where telomere gene variants are found in 20-30% of cases 1
• Premature greying (especially if onset in teens or twenties) occurs in telomeropathies as a hallmark integumentary manifestation 1, 2
• Nail dystrophy is part of the classic telomeropathy triad 1, 3
• Bone marrow failure (including aplastic anemia, myelodysplastic syndrome, or acute myeloid leukemia) strongly suggests telomere pathway involvement 1

Comprehensive Genetic Testing Approach

Order both gene sequencing and telomere length measurement, as these provide complementary information. 1

Gene Sequencing Panel

• Include RTEL1 along with other telomere genes: TERT (most common at 10-20%), TERC, PARN, DKC1, NAF1, ZCCHC8, NOP10, and TINF2 1, 2
• TERT is the most frequently mutated gene in familial pulmonary fibrosis, but RTEL1, PARN, and TERC each account for 2-5% of cases 1, 2
• Heterozygous RTEL1 mutations follow autosomal dominant inheritance with variable penetrance 1, 4

Telomere Length Testing

• Order leukocyte telomere length by flow cytometry with fluorescent in situ hybridization (flow-FISH) 1, 3
• Age-adjusted telomere length below the 1st percentile confirms dyskeratosis congenita 3
• Short telomeres are common in RTEL1-mutated patients compared to age-matched controls 4
• However, telomere length at or above the 50th percentile has negative predictive value and may argue against telomeropathy 1

Critical Pitfall to Avoid

Do not rely on telomere length alone to exclude disease, especially in patients over 40 years, as telomere shortening magnitude varies among different telomere genes and depends on age at diagnosis. 1 Normal telomere length does not perfectly discriminate between presence or absence of a rare telomere gene variant. 1

Pre-Test Evaluation

Before ordering genetic testing, complete this systematic assessment:

Three-Generation Pedigree Construction

• Document pulmonary fibrosis, bone marrow failure, liver cirrhosis, premature cancers (especially head/neck malignancy <50 years), and premature greying across at least three generations 1, 2
• Look for evidence of genetic anticipation (earlier age of onset and more severe disease in subsequent generations), which occurs in telomere gene mutation families 5

Extrapulmonary Manifestations Screen

• Hematologic: Complete blood count looking for macrocytosis, chronic anemia, thrombocytopenia, neutropenia 1, 2
• Hepatic: Liver function tests to assess for cirrhosis or liver dysfunction 1, 2
• Dermatologic: Examine for lacy reticular skin pigmentation on upper chest/neck, alopecia, oral leukoplakia 1, 3
• Skeletal: Ask about premature osteoporosis or avascular necrosis of hips/shoulders 1

Management When Pathogenic RTEL1 Variant Identified

Immediate Actions

Refer to multidisciplinary specialists immediately: pulmonology for fibrosis management, hematology for bone marrow surveillance, hepatology for liver monitoring, and medical genetics for family counseling. 2, 3

Disease-Specific Monitoring

• Pulmonary: Patients with telomere gene variants manifest various pulmonary fibrosis subtypes and are at risk for rapid progression and poor survival 1
• Hematologic: Obtain baseline bone marrow aspirate and biopsy to establish cellularity and rule out myelodysplastic syndrome 3
• Perform annual bone marrow surveillance for development of aplastic anemia or myelodysplastic syndrome 3
• Hepatic: Monitor for development of cirrhosis, as liver dysfunction is a recognized telomeropathy manifestation 1
• Oncologic: Increased surveillance for malignancies, particularly head and neck cancers before age 50 1

Genetic Counseling and Family Screening

• Offer genetic counseling to all first-degree relatives, as the presence of a disease-causing variant has implications for family members 5
• Explain autosomal dominant inheritance with variable penetrance 1, 4
• Discuss genetic anticipation, where subsequent generations may develop disease earlier and more severely 5
• Consider cascade testing of at-risk family members once a pathogenic variant is identified 5

Treatment Considerations

• Standard antifibrotic therapy (pirfenidone or nintedanib) may be used, though data specific to telomeropathy-associated pulmonary fibrosis are limited
• Avoid myelosuppressive agents given underlying bone marrow dysfunction risk 1
• Consider earlier lung transplant evaluation given risk of rapid progression 1
• Counsel about increased post-transplant complications in telomeropathy patients, including bone marrow failure and hepatic complications

Variant Interpretation Caveat

Only 38.3% of reported disease-associated RTEL1 variants meet pathogenic/likely pathogenic criteria, with 8 of 209 reported variants actually being benign or likely benign. 6 Ensure your testing laboratory uses standardized ACMG-AMP variant classification guidelines adapted for RTEL1, incorporating clinical information, telomere length data, and allele frequency. 6