title: Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita.
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.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, The Netherlands. m.jongmans@antrg.umcn.nl
authors.forename: Marjolijn C J
authors.initials: MC
authors.lastname: Jongmans
authors.forename: Eugene T P
authors.initials: ET
authors.lastname: Verwiel
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Heijdra
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Eveline J
authors.initials: EJ
authors.lastname: Kamping
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Liesbeth
authors.initials: L
authors.lastname: van Emst
authors.forename: Frank N
authors.initials: FN
authors.lastname: van Leeuwen
authors.forename: Koen L I
authors.initials: KL
authors.lastname: van Gassen
authors.forename: Ad
authors.initials: A
authors.lastname: Geurts van Kessel
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019070:Cell Lineage; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019871:Dyskeratosis Congenita / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics*; D009030:Mosaicism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000235:genetics*; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods; D019098:Telomerase / Q000235:genetics*; D055815:Young Adult
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase