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.

Exome Sequencing Identifies Mutant TINF2 in a Family With Pulmonary Fibrosis

“…Although the reversion may have protected against the bone marrow failure phenotype in the proband, to date, reversion has not been detected before the age of 40 years. 22 It is, therefore, possible that the missense mutation in this family represents a hypomorphic allele.…”

“…Somatic reversion is known to occur in genome instability syndromes and has been described in patients with dyskeratosis congenita with TR mutations. 22 In these cases, homologous recombination mediates reversion to the wild-type allele in the blood. 22 In our study, however, we found evidence suggesting an acquired clonal event in the blood.…”

“…22 In these cases, homologous recombination mediates reversion to the wild-type allele in the blood. 22 In our study, however, we found evidence suggesting an acquired clonal event in the blood. Th e mechanisms by which this occurred are unclear, but because the acquired deletion abolished the expression of the missense mutation, it may have given a growth advantage to the hematopoietic clone where it arose ( Fig 3D ).…”

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

“…De novo mutations, germline mosaicism and other complexities Although this concept of somatic mosaicism has been in the literature for many years [131][132][133][134][135], it is really only recently that more people are beginning to realize that it might be much more extensive in humans than previously thought [23,[136][137][138][139][140][141][142][143][144][145][146][147][148][149]. In fact, hardly anything is truly known regarding the extent of somatic mosaicism in humans and its effect on phenotype in even well studied diseases.…”

A Young Adult with Aplastic Anemia and Gray Hair

“…TERC and TERT mutations (5%-10% each of all cases) are found in autosomal dominant and recessive DC and show disease anticipation, such that successive generations not only inherit the genetic lesion but also have shorter telomeres, which may produce an earlier onset of clinical manifestations (8 ). Somatic reversion of the TERC gene, likely driven by a resulting selective growth advantage in hematopoietic stem cells, has been observed in DC and is a potential confounder of genetic testing (9 ). With sufficient clinical concern, a normal result in a TERC analysis of peripheral blood DNA should be followed by testing of other somatic cells.…”