A Noncanonical Splice Variant in RTEL1 Responsible for Familial Pulmonary Fibrosis

Area of Science:

• Genetics
• Pulmonology
• Molecular Biology

Background:

• Familial pulmonary fibrosis presents with variable clinical characteristics.
• Genetic variants, including those in RTEL1, are implicated in pulmonary fibrosis.
• Variants of Uncertain Significance (VUS) pose challenges in genetic diagnosis.

Purpose of the Study:

• To investigate the pathogenicity of an RTEL1 splice-region variant in a family with pulmonary fibrosis.
• To determine the role of telomere length in the disease.
• To evaluate the utility of functional studies and predictive testing in managing familial pulmonary fibrosis.

Main Methods:

• Genetic sequencing to identify variants.
• Telomere length assessment.
• mRNA and Western blot analyses to assess variant function.
• Predictive genetic testing for family members.

Main Results:

• A splice-region variant (c.3181+3A>C) in RTEL1 was identified in affected family members.
• Shortened telomeres (10th percentile) were observed.
• Functional studies helped reclassify the VUS, enabling predictive testing.

Conclusions:

• RTEL1 variants can cause familial pulmonary fibrosis with variable phenotypes.
• Functional studies are crucial for interpreting VUS and guiding clinical management.
• Predictive testing offers significant value for at-risk family members.