Reversion Mosaicism in Primary Immunodeficiency Diseases

Abstract

Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Several mechanisms can mediate somatic reversion of inherited mutations. Back mutations restore wild-type sequences, whereas second-site mutations result in compensatory changes. In addition, intragenic recombination, chromosomal deletions, and copy-neutral loss of heterozygosity have been demonstrated in mosaic individuals. Revertant cells that have regained wild-type function may be associated with milder disease phenotypes in some immunodeficient patients with reversion mosaicism. Revertant cells can also be responsible for immune dysregulation. Studies identifying a large variety of genetic changes in the same individual further support a frequent occurrence of reversion mosaicism in primary immunodeficiency diseases. This phenomenon also provides unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. In this paper, we review the recent findings of reversion mosaicism in primary immunodeficiency diseases and discuss its clinical implications.

Challenges in Gene Therapy for Somatic Reverted Mosaicism in X-Linked Combined Immunodeficiency by CRISPR/Cas9 and Prime Editing

“…Moreover, the proliferation of patients’ CD3 + T cells was impaired compared with healthy donors [ 13 ]. According to the genetic analysis, with the in vitro culturing of CD3 + T cells from patients, the frequency of the mutant base reduced over time ( Figure 1 ), which is consistent with the finding in previous studies that cells containing revertant mutation have a proliferative advantage [ 8 , 55 ]. These observations demonstrate that mutant cells are hardly capable of proliferating in vitro.…”

Recurring germline mosaicism in a family due to reversion of an inherited derivative chromosome 8 from an 8;21 translocation with interstitial telomeric sequences

“…However, spontaneous correction of a pathogenic point mutation in a somatic cell leading to wild type and mutant cell populations, which is known as revertant mosaicism or ‘natural gene therapy’ has been well-documented in Mendelian haematopoietic diseases, primary immunodeficiency diseases and other inherited disorders 3 16 17. The most common type is true reversion of the germline mutation to the wild-type sequence through a somatic point mutation 18. Other mechanisms such as chromosomal deletions, intragenic recombination and copy neutral loss of heterozygosity have been reported.…”

Extrinsic and intrinsic drivers of natural killer cell clonality

“…Clinically more favorable examples putting the spotlight on the positive selection of somatic variants in lymphocytes have been observed in the context of primary immunodeficiencies, where somatic reversion of mutant to wildtype alleles or second-site mutations can rescue immune cell development, in some cases resulting in milder phenotypes. 251 Such reverse mosaicism has been described for various primary immunodeficiencies such as adenosine deaminase (ADA) deficiency caused by mutations in ADA, 252,253 X-linked severe combined immunodeficiency (SCID) caused by mutations in IL2RG, 254 Wiskott-Aldrich syndrome (WAS) caused by mutations in WAS, [255][256][257] SCID caused by mutations in CD247, [258][259][260] or leukocyte adhesion deficiency type-1 (LAD-1) caused by mutations in ITGB2. 261 Similar to the disease-associated mutations in lymphoproliferative conditions, the cell types carrying such reversions at detectable frequencies vary widely between diseases and patients.…”