Chromothriptic cure of WHIM syndrome: Implications for bone marrow transplantation

Abstract

We recently reported a 59 year old female, designated WHIM-09, who was born with the rare immunodeficiency disease WHIM syndrome but underwent spontaneous phenotypic reversion as an adult. The causative WHIM mutation CXCR4^R334X was absent in her myeloid and erythroid lineage, but present in her lymphoid lineage and in epithelial cells, defining her as a somatic genetic mosaic. Genomic and hematologic analysis revealed chromothripsis (chromosome shattering) on one copy of chromosome 2, which deleted 164 genes including CXCR4^R334X in a single haematopoietic stem cell (HSC) (Fig. 1). Experiments in mice indicated that deleting one copy of Cxcr4 is sufficient to confer a selective advantage for engraftment of transplanted HSCs, suggesting a mechanism for clinical cure in WHIM-09. Genome editing may allow autologous transplantation of HSCs lacking one copy of CXCR4 without bone marrow conditioning as a general cure strategy in WHIM syndrome, safely recapitulating the outcome in patient WHIM-09.

Figure 1. Chromothripsis (chromosomal shattering) resulted in clinical cure of a patient with a rare immunodeficiency (WHIM syndrome) by deleting the mutant copy of CXCR4.

Keywords:

• chromothripsis
• immunodeficiency
• genetic reversion
• transplantation
• WHIM syndrome

Disclosure of Potential Conflicts of Interest

A provisional patent on CXCR4 knockdown as a method to enhance HSC engraftment has been filed by the US government with D.H.M, J.G. and P.M.M. as inventors.

Acknowledgments

We thank the research subjects for their participation in this study.

Funding

This work was supported by the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID), NIH.