title: Rare variants in RTEL1 are associated with familial interstitial pneumonia.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 1 Division of Medical Genetics and Genomic Medicine, Department of Pediatrics.
authors.forename: Joy D
authors.initials: JD
authors.lastname: Cogan
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kropski
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Daphne B
authors.initials: DB
authors.lastname: Mitchell
authors.forename: Lynette
authors.initials: L
authors.lastname: Rives
authors.forename: Cheryl
authors.initials: C
authors.lastname: Markin
authors.forename: Errine T
authors.initials: ET
authors.lastname: Garnett
authors.forename: Keri H
authors.initials: KH
authors.lastname: Montgomery
authors.forename: Wendi R
authors.initials: WR
authors.lastname: Mason
authors.forename: David F
authors.initials: DF
authors.lastname: McKean
authors.forename: Julia
authors.initials: J
authors.lastname: Powers
authors.forename: Elissa
authors.initials: E
authors.lastname: Murphy
authors.forename: Lana M
authors.initials: LM
authors.lastname: Olson
authors.forename: Leena
authors.initials: L
authors.lastname: Choi
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.forename: Elizabeth Marchani
authors.initials: EM
authors.lastname: Blue
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Lancaster
authors.forename: Mark P
authors.initials: MP
authors.lastname: Steele
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.forename: Marvin I
authors.initials: MI
authors.lastname: Schwarz
authors.forename: Tasha E
authors.initials: TE
authors.lastname: Fingerlin
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
authors.forename: William E
authors.initials: WE
authors.lastname: Lawson
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008168:Lung / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D016615:Telomere / Q000235:genetics
chemical_list: C532890:RTEL1 protein, human; D004265:DNA Helicases
keywords: genetics; idiopathic pulmonary fibrosis; telomere