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Am. J. Respir. Crit. Care Med. · Mar 2015
Rare Variants in RTEL1 are Associated with Familial Interstitial Pneumonia.
- Joy D Cogan, Jonathan A Kropski, Min Zhao, Daphne B Mitchell, Lynette Rives, Cheryl Markin, Errine T Garnett, Keri H Montgomery, Wendi R Mason, David F McKean, Julia Powers, Elissa Murphy, Lana M Olson, Leena Choi, Dong-Sheng Cheng, Elizabeth Marchani Blue, Lisa R Young, Lisa H Lancaster, Mark P Steele, Kevin K Brown, Marvin I Schwarz, Tasha E Fingerlin, David A Schwartz, William E Lawson, James E Loyd, Zhongming Zhao, John A Phillips, and Timothy S Blackwell.
- 1 Division of Medical Genetics and Genomic Medicine, Department of Pediatrics.
- Am. J. Respir. Crit. Care Med. 2015 Mar 15; 191 (6): 646655646-55.
RationaleUp 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.ObjectivesTo 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.MethodsAffected 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 ResultsWe 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.ConclusionsRare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.
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