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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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Jongmans MC,Verwiel ET,Heijdra Y,Vulliamy T,Kamping EJ,Hehir-Kwa JY,Bongers EM,Pfundt R,van Emst L,van Leeuwen FN,van Gassen KL,Geurts van Kessel A,Dokal I,Hoogerbrugge N,Ligtenberg MJ,Kuiper RP

doi

10.1016/j.ajhg.2012.01.004

subject

Has Abstract

pub_date

2012-03-09 00:00:00

pages

426-33

issue

3

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(12)00036-5

journal_volume

90

pub_type

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