Clonal hematopoiesis in patients with dyskeratosis congenita

Abstract

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. Additionally, 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.

Clinical consequences of clonal hematopoiesis of indeterminate potential

“…Individuals with short telomeres, whether due to well-defined syndromes, such as dyskeratosis congenita, or to lesspenetrant polymorphisms in telomere components (and 1 polymorphism in a telomere-associated gene is associated with higher risk for developing clonal hematopoiesis 7 ), may develop clonal evolution as a result of gross chromosomal instability consequent to failed DNA damage checkpoint function in critically short telomeres. 42 What other factors contribute to CHIP progression?…”

The genomics of inherited bone marrow failure: from mechanism to the clinic

“…In the IBMFS, as well as in acquired aplastic anaemia and MDS, NGS is being used to identify somatic mutations that may be associated with disease progression and clinical outcomes (Kulasekararaj et al , ; Fernandez‐Pol et al , ). Such studies have also been used to quantify the degree of clonal haematopoiesis in patients with aplastic anaemia and in DC (Babushok et al , ; Yoshizato et al , ; Perdigones et al , ).…”

Insights from human genetic studies of lung and organ fibrosis

“…Somatic genetic variants, which are acquired over time, may provide an explanation for variable expressivity of phenotypes. Skewed X-inactivation, revertant mosaicism, and clonal hematopoiesis can be seen in patients with dyskeratosis congenita (125)(126)(127). In these cases, the somatic change results in the correction or deletion of the pathogenic allele.…”