Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis

Chest. 2020 Dec;158(6):2449-2457. doi: 10.1016/j.chest.2020.07.025. Epub 2020 Jul 22.


Background: Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline.

Research question: What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient?

Study design and methods: We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family.

Results: We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease.

Interpretation: Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis.

Keywords: bone marrow failure; lung transplantation; telomerase.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Bone Marrow Failure Disorders* / blood
  • Bone Marrow Failure Disorders* / diagnosis
  • Cell Cycle Proteins / genetics*
  • Fatal Outcome
  • Humans
  • Idiopathic Pulmonary Fibrosis* / diagnosis
  • Idiopathic Pulmonary Fibrosis* / genetics
  • Idiopathic Pulmonary Fibrosis* / physiopathology
  • Idiopathic Pulmonary Fibrosis* / therapy
  • Lung Transplantation* / adverse effects
  • Lung Transplantation* / methods
  • Male
  • Nuclear Proteins / genetics*
  • Pedigree
  • Phylogeny
  • Postoperative Complications / diagnosis*
  • RNA / genetics*
  • Sepsis* / diagnosis
  • Sepsis* / etiology
  • Silent Mutation
  • Skin Neoplasms / pathology
  • Telomerase / genetics*
  • Telomere Homeostasis / genetics
  • Whole Genome Sequencing / methods


  • Cell Cycle Proteins
  • DKC1 protein, human
  • Nuclear Proteins
  • telomerase RNA
  • RNA
  • Telomerase