title: Telomere length is associated with disease severity and declines with age in dyskeratosis congenita.
abstract: BACKGROUND
  Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology.
  
  
  METHODS
  We studied 65 patients with dyskeratosis congenita and 127 unaffected relatives. Telomere length was measured by automated multicolor flow fluorescence in situ hybridization in peripheral blood leukocyte subsets. We age-adjusted telomere length using Z-scores (standard deviations from the mean for age).
  
  
  RESULTS
  We confirmed that telomere lengths below the first percentile for age are very sensitive and specific for the diagnosis of dyskeratosis congenita. We provide evidence that lymphocytes alone and not granulocytes may suffice for clinical screening, while lymphocyte subsets may be required for challenging cases, including identification of silent carriers. We show for the first time using flow fluorescence in situ hybridization that the shortest telomeres are associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes), mutations in DKC1, TINF2, or unknown genes, and moderate or severe aplastic anemia. In the first longitudinal follow up of dyskeratosis congenita patients, we demonstrate that telomere lengths decline with age, in contrast to the apparent stable telomere length observed in cross-sectional data.
  
  
  CONCLUSIONS
  Telomere length by flow fluorescence in situ hybridization is an important diagnostic test for dyskeratosis congenita; age-adjusted values provide a quantitative measure of disease severity (clinical subset, mutated gene, and degree of bone marrow failure). Patients with dyskeratosis congenita have accelerated telomere shortening. This study is registered at www.clinicaltrials.gov (identifier: NCT00027274).
authors: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20852-7231, USA. alterb@mail.nih.gov
authors: Blanche P
authors: BP
authors: Alter
authors: Philip S
authors: PS
authors: Rosenberg
authors: Neelam
authors: N
authors: Giri
authors: Gabriela M
authors: GM
authors: Baerlocher
authors: Peter M
authors: PM
authors: Lansdorp
authors: Sharon A
authors: SA
authors: Savage
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D019871:Dyskeratosis Congenita / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D059506:Telomere Shortening; D055815:Young Adult