• Valeriya Gaysinskaya, Susan E Stanley, Soheir Adam, and Mary Armanios.
• Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; Telomere Center, Johns Hopkins University School of Medicine, Baltimore, MD.
• Chest. 2020 Dec 1; 158 (6): 2449-2457.

BackgroundIdiopathic 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 QuestionWhat is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient?Study Design And MethodsWe analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family.ResultsWe 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.InterpretationOur 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.Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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