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Somatic genetic rescue in Mendelian haematopoietic diseases


Somatic mutations occur spontaneously in normal individuals and accumulate throughout life. These genetic modifications contribute to progressive ageing phenotypes and are directly involved in cancer development. However, a growing number of studies of Mendelian haematopoietic disorders indicate that somatic genetic events can offset the pathogenic effect of germline mutations at the cellular level, leading to genetic mosaicism and, in some cases, resulting in a milder disease phenotype. Notably, spontaneous genetic events that confer a positive effect on cells do not always benefit the individual, for whom the effects can be neutral or even clinically detrimental. These somatic genetic rescue events have important diagnostic, therapeutic and clinical consequences and constitute valuable models for studying the differentiation and/or homeostasis of haematopoietic lineages.

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Despite efforts to be as exhaustive as possible, the authors apologize to all colleagues whose work is not cited because of space limitations. P.R. warmly thanks J.P. de Villartay and S. Latour for discussions, advice and support, and also thanks the members of the DGSI laboratory. Current work in P.R.’s laboratory is funded by INSERM, Ligue contre le Cancer and INCa. P.R. is a staff scientist at the Centre National de la Recherche Scientifique (CNRS).

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Nature Reviews Genetics thanks F. Candotti, D. Schindler, H.S. Scott and P. Venugopal for their contribution to the peer review of this work.

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P.R. and A.F. contributed to all aspects of the article. C.K. reviewed the manuscript before submission.

Correspondence to Patrick Revy.

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Somatic mosaicism

Occurs when an individual contains two or more genetically distinct cellular populations that initially arose from the same fertilized egg.

Biallelic mutations

Two (possibly different) mutations located on both alleles of the same gene.

Interstitial deletions

Losses of an internal part of a chromosome.


Complex genomic modification characterized by a high number of chromosomal rearrangements and copy number changes in one or a small number of chromosomes.

Compound heterozygosity

The existence of distinct mutations on opposite alleles of a single gene.

AluY motifs

Short, interspersed and repeated sequences integrated into the genome.

Genomic instability

Increased rate of genomic mutation.

Uniparental disomy

Occurs when both copies of a chromosome originate from one parent (maternal or paternal) and the chromosome from the other parent is absent. Segmental uniparental disomy occurs when only part of a chromosome is affected.


An abnormal chromosome number resulting from gain or a loss of one or a few chromosomes or arms of a chromosome.

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Fig. 1: Somatic mutations in the haematopoietic system.
Fig. 2: SGR mechanisms as a function of germline mutation.
Fig. 3: Schematic representation of the different point mutations that can lead to SGR.
Fig. 4: Examples of indirect SGR.
Fig. 5: Somatic mosaicism in the haematopoietic system caused by SGR of a Mendelian haematological disease.