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Mean leucocyte telomere length (LTL) has been associated with cancer and several age-associated diseases. Common variants within or near genes known to be involved in telomere biology (TERT, TERC, RTEL1) have been associated with mean LTLs in genome-wide association studies (GWAS).1 ,2 Rare variants in these genes have also been found to cosegregate with short telomere lengths and lung disease in familial pulmonary fibrosis kindreds.3–5 Rare variants in an additional telomere-related gene, PARN (polyadenylation-specific ribonuclease deadenylation nuclease), were recently found by exome sequencing older adults with familial pulmonary fibrosis3 as well as patients with dyskeratosis congenita, a disorder of telomere biology generally affecting children.6 ,7 PARN has not been identified by GWAS studies as a contributor of human telomere length regulation. Here we determine if the PARN locus could have been identified using genome-wide linkage analysis of LTLs in one large familial pulmonary fibrosis kindred that has a cosegregating PARN nonsense mutation.
This study was approved by the institutional review board at the University of Texas Southwestern Medical Center. Written informed consent was obtained from all available family participants, who were recruited from 2006 to 2010 as previously described.3 A heterozygous loss of function PARN mutation (c.529C>T, Gln177*) cosegregates with pulmonary fibrosis in the kindred shown in figure 1A. The proband (III:10) died at the age of 43 of complications of progressive pulmonary fibrosis; his mean LTL (as measured by a QPCR assay3) was <1st percentile as compared with age-matched controls. …
Contributors Both authors contributed to the design of the study, performed genetic analyses and directed experiments.
Funding US National Institute for Health Heart, Lung and Blood Institute and the National Center for Advancing Translational Science (HL093096 and UL1TR001105).
Competing interests None declared.
Ethics approval University of Texas Southwestern Medical Center.
Provenance and peer review Not commissioned; externally peer reviewed.