|Title||Rare variants in RTEL1 are associated with familial interstitial pneumonia.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Cogan, JD, Kropski, JA, Zhao, M, Mitchell, DB, Rives, L, Markin, C, Garnett, ET, Montgomery, KH, Mason, WR, McKean, DF, Powers, J, Murphy, E, Olson, LM, Choi, L, Cheng, D-S, Blue, EMarchani, Young, LR, Lancaster, LH, Steele, MP, Brown, KK, Schwarz, MI, Fingerlin, TE, Schwartz, DA, Lawson, WE, Loyd, JE, Zhao, Z, Phillips, JA, Blackwell, TS|
|Journal||Am J Respir Crit Care Med|
|Date Published||2015 Mar 15|
|Keywords||Aged, Aged, 80 and over, DNA Helicases, Female, Genetic Variation, Heterozygote, Humans, Lung, Lung Diseases, Interstitial, Male, Middle Aged, Pedigree, Telomere|
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 (
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.
|Alternate Journal||Am. J. Respir. Crit. Care Med.|
|PubMed Central ID||PMC4384777|
|Grant List||P01 HL092870 / HL / NHLBI NIH HHS / United States |
HL085317 / HL / NHLBI NIH HHS / United States
HL92870 / HL / NHLBI NIH HHS / United States
U01 HG007674 / HG / NHGRI NIH HHS / United States
R01 HL105479 / HL / NHLBI NIH HHS / United States
T32 HL094296 / HL / NHLBI NIH HHS / United States
R01 HL085317 / HL / NHLBI NIH HHS / United States
I01 BX001988 / BX / BLRD VA / United States
HL094296 / HL / NHLBI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 HL097163 / HL / NHLBI NIH HHS / United States
UL1 RR024975 / RR / NCRR NIH HHS / United States
1U54HG006493 / HG / NHGRI NIH HHS / United States
HL105479 / HL / NHLBI NIH HHS / United States
HL0097163 / HL / NHLBI NIH HHS / United States
R01 HL119503 / HL / NHLBI NIH HHS / United States