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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1439-1447.
Prepublished online as a Blood First Edition Paper on April 27, 2007; DOI 10.1182/blood-2007-02-075598.
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CLINICAL TRIALS AND OBSERVATIONS
Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita
Blanche P. Alter1,
Gabriela M. Baerlocher2,
Sharon A. Savage1,
Stephen J. Chanock3,
Babette B. Weksler4,
Judith P. Willner5,
June A. Peters1,
Neelam Giri1, and
Peter M. Lansdorp6
1 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD;
2 Hematology, University Hospital, Berne, Switzerland;
3 Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD;
4 Department of Medicine, Weill Medical College, New York, NY;
5 Department of Genetics, Mount Sinai School of Medicine, New York, NY;
6 Terry Fox Laboratory, British Columbia Cancer Research Center, Vancouver, Canada
Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome in which the known susceptibility genes (DKC1, TERC, and TERT) belong to the telomere maintenance pathway; patients with DC have very short telomeres. We used multicolor flow fluorescence in situ hybridization analysis of median telomere length in total blood leukocytes, granulocytes, lymphocytes, and several lymphocyte subsets to confirm the diagnosis of DC, distinguish patients with DC from unaffected family members, identify clinically silent DC carriers, and discriminate between patients with DC and those with other bone marrow failure disorders. We defined "very short" telomeres as below the first percentile measured among 400 healthy control subjects over the entire age range. Diagnostic sensitivity and specificity of very short telomeres for DC were more than 90% for total lymphocytes, CD45RA+/CD20– naive T cells, and CD20+ B cells. Granulocyte and total leukocyte assays were not specific; CD45RA– memory T cells and CD57+ NK/NKT were not sensitive. We observed very short telomeres in a clinically normal family member who subsequently developed DC. We propose adding leukocyte subset flow fluorescence in situ hybridization telomere length measurement to the evaluation of patients and families suspected to have DC, because the correct diagnosis will substantially affect patient management.
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