Skewed X-Inactivation in Carriers of X-Linked Dyskeratosis Congenita

Vulliamy, Thomas J.; Knight, Stuart W.; Dokal, Inderjeet; Mason, Philip J.

doi:10.1182/blood.v90.6.2213

Cited by 61 publications

(24 citation statements)

References 16 publications

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“…Finally, because female carriers of DKC1 mutations frequently develop biased X‐inactivation due to the growth advantage of WT DKC1 ‐expressing cells , we performed the X chromosome inactivation analysis with the HUMARA assay to look for evidence of skewed X‐inactivation in peripheral blood of the patient's mother. Taking advantage of the microsatellite allele of the human androgen receptor shared between the patient and his mother as a marker of co‐segregating mutant DKC1 , we found that the mother's X‐inactivation was strongly biased towards expression of the WT DKC1 allele (Fig.…”

Section: Resultsmentioning

confidence: 99%

Clonal hematopoiesis in patients with dyskeratosis congenita

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 99%

Clonal hematopoiesis in patients with dyskeratosis congenita

et al. 2016

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“…The proband was heterozygous for the DKC1 G486R polymorphism (rs150319104; minor allele frequency in 1,000 genomes ¼ 0.001). Normally females heterozygous for pathogenic DKC1 mutations have no phenotype or are only very mildly affected, but all female carriers of disease causing DKC1 mutations show extreme skewing of X-inactivation owing to a competitive advantage of cells expressing the wild-type allele following random X-inactivation [7]. We reasoned that a sensitive test for the status of the DKC1 G486R mutation would be to test the mother, who is heterozygous for the mutation, for skewed X-inactivation.…”

Section: Case Reportmentioning

confidence: 99%

A family with Hoyeraal–Hreidarsson syndrome and four variants in two genes of the telomerase core complex

Vogiatzi¹,

Perdigones²,

Mason³

et al. 2013

Pediatric Blood & Cancer

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We describe an African American family with Hoyeraal Hreidarrson syndrome (HHS) in which 2 TERT mutations (causing P530L and A880T amino acid changes) and two in the DKC1 variants (G486R and A487A) were segregating. Both genes are associated with dyskeratosis congenita and HHS. It was important to determine the importance of these mutations in disease pathogenesis to counsel family members. From genetic analysis of family members, telomere length and X-inactivation studies we concluded that compound heterozygosity for the TERT mutations was the major cause of HHS and the DKC1 G486R variant is a rare African variant unlikely to cause disease.

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“…The situation is different when there is a selective disadvantage for the cell that carries the mutant allele on the active X chromosome. This is the case for carriers of several severe X‐linked disorders, such as Wiskott–Aldrich syndrome 42, α‐thalassaemia/mental retardation syndrome 43, dyskeratosis congenita 4445 and Barth syndrome 46. In these disorders, post‐inactivation selection probably takes place, leading to a completely skewed X‐inactivation pattern and a normal phenotype.…”

Section: Inactivation In Different Tissuesmentioning

confidence: 99%

Skewed X inactivation in healthy individuals and in different diseases

Ørstavik¹

2006

Acta Paediatrica

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In female mammalian cells, one of the two X chromosomes is inactivated in early embryonic life. Females are mosaics for two cell populations, one with the maternal and one with the paternal X as the active chromosome. Skewed X inactivation is arbitrarily defined, often as a pattern where 80% or more of the cells show a preferential inactivation of one X chromosome. Inactivation is presumed to be permanent for all descendants of a cell; however, after about 55 years of age, the frequency of skewed X inactivation in peripheral blood cells increases, probably through selection. Unfavourable skewing of X inactivation, where the X chromosome carrying a mutant allele is the predominantly active X, has been found in affected female carriers of several X‐linked disorders; however, for many X‐linked disorders, a consistent relationship between the pattern of X inactivation and clinical phenotype has been difficult to demonstrate. One reason for this may be that peripheral blood cells are not a representative or relevant tissue in many disorders. In some severe X‐linked disorders, post‐inactivation selection takes place against the X chromosome carrying the mutant allele, leading to a completely skewed X‐inactivation pattern. Skewed X inactivation has also been reported in young females with breast cancer, and may indicate an effect of X‐linked genes on the development of this condition. Conclusion: The process of X inactivation and the resultant degree of skewing is clearly important for the expression of genetic diseases. It is also important to consider, however, that under normal conditions the frequency of skewed X inactivation increases with age in peripheral blood cells. Analysis of the expression of a large proportion of the genes on the X chromosome has revealed that X‐chromosome inactivation is more heterogeneous than previously thought.

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Skewed X-Inactivation in Carriers of X-Linked Dyskeratosis Congenita

Cited by 61 publications

References 16 publications

Clonal hematopoiesis in patients with dyskeratosis congenita

Clonal hematopoiesis in patients with dyskeratosis congenita

A family with Hoyeraal–Hreidarsson syndrome and four variants in two genes of the telomerase core complex

Skewed X inactivation in healthy individuals and in different diseases

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