Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene.
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.
Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Jonathan K
JK
Alder
Erin M
EM
Parry
Srinivasan
S
Yegnasubramanian
Christa L
CL
Wagner
Lawrence M
LM
Lieblich
Robert
R
Auerbach
Arleen D
AD
Auerbach
Sarah J
SJ
Wheelan
Mary
M
Armanios
D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics*; D019871:Dyskeratosis Congenita / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010641:Phenotype; D016415:Sequence Alignment; D016615:Telomere / Q000235:genetics*
D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins
DKC1; Dyskeratosis congenita; myelodysplastic syndrome; pulmonary fibrosis; telomerase