Clonal hematopoiesis in patients with dyskeratosis congenita.
Dyskeratosis congenita (DC) is a rare inherited telomeropathy most frequently caused by mutations in a number of genes all thought to be involved in telomere maintenance. The main causes of mortality in DC are bone marrow failure as well as malignancies including leukemias and solid tumors. The clinical picture including the degree of bone marrow failure is highly variable and factors that contribute to this variability are poorly understood. Based on the recent finding of frequent clonal hematopoiesis in related bone marrow failure syndromes, we hypothesized that somatic mutations may also occur in DC and may contribute at least in part to the variability in blood production. To evaluate for the presence of clonal hematopoiesis in DC, we used a combination of X-inactivation, comparative whole exome sequencing (WES) and single nucleotide polymorphism array (SNP-A) analyses. We found that clonal hematopoiesis in DC is common, as suggested by skewed X-inactivation in 8 out of 9 female patients compared to 3 out of 10 controls, and by the finding of acquired copy neutral loss-of-heterozygosity on SNP-A analysis. In addition, 3 out of 6 independent DC patients were found to have acquired somatic changes in their bone marrow by WES, including a somatic reversion in DKC1, as well as missense mutations in other protein coding genes. Our results indicate that clonal hematopoiesis is a common feature of DC, and suggest that such somatic changes, though commonly expected to indicate malignancy, may lead to improved blood cell production or stem cell survival. Am. J. Hematol. 91:1227-1233, 2016. © 2016 Wiley Periodicals, Inc.
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104.
Nieves
N
Perdigones
Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104.
Juan C
JC
Perin
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104.
Irene
I
Schiano
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104.
Peter
P
Nicholas
Children's Hospital Los Angeles and Keck School of Medicine at the University of Southern California, Los Angeles, California, 90027.
Jaclyn A
JA
Biegel
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104.
Philip J
PJ
Mason
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104.|Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, 19104.
Daria V
DV
Babushok
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104.|Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, 19104.
Monica
M
Bessler
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002999:Clone Cells / Q000473:pathology*; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000473:pathology; D005260:Female; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D007223:Infant; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D049951:X Chromosome Inactivation; D055815:Young Adult