Rare Variants in RTEL1 Are Associated with Familial Interstitial Pneumonia

Abstract

Rationale: Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.Objectives: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds. Measurements and Main Results:We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (,10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function.Conclusions: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

“…22,34,35 However, none of the patients in our series presented with such features, probably because of their young age. Although the patients' parents have not developed pulmonary fibrosis so far, they should probably avoid exposure to environmental stress (eg, smoking, fibrogenic dust inhalation) and be followedup by a pulmonologist.…”

Myelodysplasia and liver disease extend the spectrum of RTEL1 related telomeropathies

“…However, we now note that these individuals may nevertheless be predisposed to developing disease in their later years. This is suggested by Family 2 ( Figure 1A, p.G1096W) where there is a history of pulmonary disease in the grandmother in her 70s and for the p.R998* variant, which has been seen in both severe recessive 3,5,6 and late onset dominant settings (Families 4 and 8 and Cogan et al 7 ). Thus, it is important to be careful when counselling families.…”

Management of suspected monogenic lung fibrosis in a specialised centre

“…Mutations in DKC1, NAF1 and TINF2 are much rarer (figure 1) [9,23,[28][29][30][31][32][33][34][35]. TERT or TERC mutations may be found in about 1-3% of sporadic IPF cases [28].…”