Title: | Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. |
Author(s): | Jongmans, M.C.J. ; Verwiel, E.T.P. ; Heijdra, Y.F. ; Vulliamy, T.; Kamping, E.J. ; Hehir, J.Y. ; Bongers, M.H.F. ; Pfundt, R.; Emst, J.E. van ; Leeuwen, F.N. van ; Gassen, K.L.I. van ; Geurts van Kessel, A.H.M. ; Dokal, I.; Hoogerbrugge-van der Linden, N. ; Ligtenberg, M.J.L. ; Kuiper, R.P. |
Publication year: | 2012 |
Source: | American Journal of Human Genetics, vol. 90, iss. 3, (2012), pp. 426-433 |
ISSN: | 0002-9297 |
DOI: | https://doi.org/10.1016/j.ajhg.2012.01.004 |
Publication type: | Article / Letter to editor |
Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/109400 ![]() |
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Subject: | IGMD 3: Genomic disorders and inherited multi-system disorders IGMD 9: Renal disorder N4i 1: Pathogenesis and modulation of inflammation NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders NCMLS 6: Genetics and epigenetic pathways of disease ONCOL 3: Translational research ONCOL 1: Hereditary cancer and cancer-related syndromes ONCOL 1: Hereditary cancer and cancer-related syndromes NCMLS 6: Genetics and epigenetic pathways of disease ONCOL 2: Age-related aspects of cancer NCMLS 2: Immune Regulation Tijdelijke code tbv inlezen publicaties Radboudumc - Alleen voor gebruik door Radboudumc |
Organization: | Human Genetics Pulmonary Diseases Dermatology Paediatrics - OUD tm 2017 Laboratory of Genetic, Endocrine and Metabolic Diseases Medical Oncology Pathology |
Journal title: |
American Journal of Human Genetics
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Volume: | vol. 90 |
Issue: | iss. 3 |
Page start: | p. 426 |
Page end: | p. 433 |
Abstract: |
Revertant mosaicism is an infrequently observed phenomenon caused by spontaneous correction of a pathogenic allele. We have observed such reversions caused by mitotic recombination of mutant TERC (telomerase RNA component) alleles in six patients from four families affected by dyskeratosis congenita (DC). DC is a multisystem disorder characterized by mucocutaneous abnormalities, dystrophic nails, bone-marrow failure, lung fibrosis, liver cirrhosis, and cancer. We identified a 4 nt deletion in TERC in a family with an autosomal-dominant form of DC. In two affected brothers without bone-marrow failure, sequence analysis revealed pronounced overrepresentation of the wild-type allele in blood cells, whereas no such skewing was observed in the other tissues tested. These observations suggest that this mosaic pattern might have resulted from somatic reversion of the mutated allele to the normal allele in blood-forming cells. SNP-microarray analysis on blood DNA from the two brothers indeed showed independent events of acquired segmental isodisomy of chromosome 3q, including TERC, indicating that the reversions must have resulted from mitotic recombination events. Subsequently, after developing a highly sensitive method of detecting mosaic homozygosity, we have found four additional cases with a mosaic-reversion pattern in blood cells; these four cases are part of a cohort of 17 individuals with germline TERC mutations. This shows that revertant mosaicism is a recurrent event in DC. This finding has important implications for improving diagnostic testing and understanding the variable phenotype of DC.
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