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Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2012 Mar 09; Vol. 90 (3), pp. 426-33. Date of Electronic Publication: 2012 Feb 16. - Publication Year :
- 2012
-
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.<br /> (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adolescent
Adult
Aged
Alleles
Cell Lineage
Child
Child, Preschool
Cohort Studies
Female
Germ-Line Mutation
Homozygote
Humans
Male
Middle Aged
Pedigree
Polymorphism, Single Nucleotide
Sequence Analysis, DNA methods
Young Adult
Dyskeratosis Congenita genetics
Mitosis genetics
Mosaicism
RNA genetics
Recombination, Genetic
Telomerase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 90
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 22341970
- Full Text :
- https://doi.org/10.1016/j.ajhg.2012.01.004