RAG1 Reversion Mosaicism in a Patient with Omenn Syndrome
E Crestani, S Choo, F Frugoni, YN Lee… - Journal of clinical …, 2014 - Springer
E Crestani, S Choo, F Frugoni, YN Lee, S Richards, J Smart, LD Notarangelo
Journal of clinical immunology, 2014•SpringerPurpose To identify mechanisms of disease in a child born to consanguineous parents, who
presented with Omenn syndrome (OS) and was found to carry a heterozygous RAG1
mutation in peripheral blood DNA. Methods Mutation analysis was performed on whole
blood and buccal swab DNA. Recombination activity of the mutant RAG1 protein and
diversity of T cell repertoire were tested. Results Apparent heterozygosity for a novel,
functionally null RAG1 mutation in peripheral blood DNA from a patient with OS was shown …
presented with Omenn syndrome (OS) and was found to carry a heterozygous RAG1
mutation in peripheral blood DNA. Methods Mutation analysis was performed on whole
blood and buccal swab DNA. Recombination activity of the mutant RAG1 protein and
diversity of T cell repertoire were tested. Results Apparent heterozygosity for a novel,
functionally null RAG1 mutation in peripheral blood DNA from a patient with OS was shown …
Purpose
To identify mechanisms of disease in a child born to consanguineous parents, who presented with Omenn syndrome (OS) and was found to carry a heterozygous RAG1 mutation in peripheral blood DNA.
Methods
Mutation analysis was performed on whole blood and buccal swab DNA. Recombination activity of the mutant RAG1 protein and diversity of T cell repertoire were tested.
Results
Apparent heterozygosity for a novel, functionally null RAG1 mutation in peripheral blood DNA from a patient with OS was shown to be secondary to true somatic reversion. Analysis of T cell repertoire demonstrated expression of various TCRBV families, but an overall restricted pattern.
Conclusions
This is the first case of true somatic reversion of a RAG1 mutation in a patient with OS. The reversion event likely occurred at a stage where only a limited pool of T cell progenitors capable of performing V(D)J recombination could be generated. This work emphasizes the importance of performing functional studies to investigate the significance of novel genetic variants, and to consider somatic reversion as a possible disease modifier in SCID.
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