Contract grant sponsors: United States National Institutes of Health (NIH) (RO1CA160433, K99HL113105); Doris Duke Charitable Foundation; NIH (P30CA006973).
Telomere Phenotypes in Females with Heterozygous Mutations in the Dyskeratosis Congenita 1 (DKC1) Gene
Article first published online: 11 SEP 2013
© 2013 WILEY PERIODICALS, INC.
Volume 34, Issue 11, pages 1481–1485, November 2013
How to Cite
Alder, J. K., Parry, E. M., Yegnasubramanian, S., Wagner, C. L., Lieblich, L. M., Auerbach, R., Auerbach, A. D., Wheelan, S. J. and Armanios, M. (2013), Telomere Phenotypes in Females with Heterozygous Mutations in the Dyskeratosis Congenita 1 (DKC1) Gene. Hum. Mutat., 34: 1481–1485. doi: 10.1002/humu.22397
Communicated by Dominique Stoppa-Lyonnet
- Issue published online: 9 OCT 2013
- Article first published online: 11 SEP 2013
- Accepted manuscript online: 14 AUG 2013 09:32AM EST
- Manuscript Accepted: 7 AUG 2013
- Manuscript Received: 10 APR 2013
- United States National Institutes of Health (NIH). Grant Numbers: RO1CA160433, K99HL113105
- Doris Duke Charitable Foundation
- NIH. Grant Number: P30CA006973
- Dyskeratosis congenita;
- pulmonary fibrosis;
- myelodysplastic syndrome
Dyskeratosis congenita (DC) is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of DC, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes, showing skewed X-inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing penetrant telomere phenotypes that, at times, may be associated with clinical morbidity.