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Exome Sequencing Study Links Variants in Two Genes to Familial Pulmonary Fibrosis

NEW YORK (GenomeWeb) – Researchers from the University of Texas Southwestern Medical Center and elsewhere have linked variants within two genes to familial pulmonary fibrosis.

As they reported in Nature Genetics today, the researchers performed exome sequencing on nearly a hundred people with age-related familial pulmonary fibrosis, and through a gene burden analysis of cases and controls homed in on variants in PARN and RTEL1 as linked to the disease. Carriers of these mutations, UT-Southwestern's Christine Kim Garcia and her colleagues added, tended to have shortened telomeres, which has been linked to worse survival in people with the sporadic form of the disease.

"The identification of two new genes contributing to this trait strengthens the link between telomere attrition and lung fibrosis and describes a new gene required for telomere maintenance," the researchers wrote in their paper.

Garcia and her colleagues sequenced the exomes of 99 people with idiopathic pulmonary fibrosis. They then focused on the 78 patients who clustered through a principal components analysis with HapMap subjects of European ancestry and compared their sequences to those of 2,816 controls of European ancestry.

By focusing their search on variants that were likely to affect the function of the proteins encoded in the sequence, like premature termination, frameshift, and splice-site mutations, the researchers found two genes — PARN and RTEL1 — that reached genome-wide significance.

Probands in this study, the researchers noted, harbored six heterozygous damaging variants in PARN, which they confirmed through Sanger sequencing, while controls had none. PARN, the researchers added, encodes a 3'exoribonuclease.

However, two of the PARN variants, the researchers realized, were identical by descent — two of the research participants were distantly related, sharing a great-grandmother — meaning they found five independent new, damaging PARN mutations, which they noted, was still highly significant.

All five of these loss-of-function variants affect residues within the CAF1 ribonuclease domain, a region that is conserved from yeast and makes up a critical part of a cytoplasmic deadenylase.

At the same time, Garcia and her colleagues uncovered five new heterozygous variants — two damaging and three missense variants at highly conserved spots — in RTEL1 in individuals with pulmonary fibrosis.

However, they also found some RTEL1 variants among controls, though there were more damaging and missense variants at conserved residues among cases than controls. Still, five mutation carriers were disease-free, which the researchers said suggests incomplete penetrance of the disease.

RTEL1, Garcia and her colleagues added, encodes an N-terminal helicase domain that helps preserve telomere length during replication. Two of the rare RTEL1 variants are predicted to be loss-of-function alleles that affect a highly conserved RAD3-related DNA helicase domain.

Using terminal restriction fragment length analysis and qPCR, the researchers also gauged the telomere lengths of genomic DNA isolated from circulating leukocytes. Probands with PARN and RTEL1 mutations, they found, had shorter mean telomere lengths than their unrelated, unaffected spouses.

Family members of the probands who did not inherit PARN and RTEL1 mutations also had shorter telomeres, on average, than their spouses, but longer than their mutation-carrying relatives. This, the researchers noted, is consistent with the genetic and epigenetic inheritance of telomere lengths.

All together, the researchers said, these studies implicate a role for rare, heterozygous loss-of-function variants in the PARN and RTEL1 genes in pulmonary fibrosis that's associated with shortened telomeres. They noted, though, that the mechanism through which PARN is involved in telomere shortening is unknown.

"Together, these genes explain [about] 7 percent of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction," Garcia and her colleagues added.