ID
45957
Description
Principal Investigator: Philip M. Murphy, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA MeSH: WHIM syndrome,Warts,Severe congenital neutropenia,Hypogammaglobulinemia,Warts, hypogammaglobulinemia, infections, and myelokathexis https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000856 We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor *CXCR4*. We have identified a patient born with WHIM syndrome and the WHIM mutation *CXCR4supR334X/sup* who has been disease-free for 20 years and who lacks *CXCR4supR334X/sup* in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele *CXCR4supR334X/sup* and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective *Cxcr4* haploinsufficiency (inactivation of one copy of *Cxcr4* and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that *CXCR4* knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.
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- 3/16/24 3/16/24 - Madita Rudolph
Copyright Holder
Philip M. Murphy, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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March 16, 2024
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Creative Commons BY 4.0
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dbGaP phs000856 Chromothripsis in Patient WHIM-09
Eligibility Criteria
- StudyEvent: SEV1
- Eligibility Criteria
- This data table contains mapping of study subject IDs to sample IDs. Samples are the final preps submitted for genotyping, sequencing, and/or expression data. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. The data table also includes sample use.
- This subject consent data table contains a subject ID, consent group information, and affection status for a single WHIM patient.
- This sample attributes data table includes body site where sample was collected, analyte type, tumor status, and sequencing center.
- This subject phenotype data table contains disease onset age, height at enrollment, birthplace, sex, race, CXCR4 status, age, and presence of clinical characteristics of WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis).
Similar models
Eligibility Criteria
- StudyEvent: SEV1
- Eligibility Criteria
- This data table contains mapping of study subject IDs to sample IDs. Samples are the final preps submitted for genotyping, sequencing, and/or expression data. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. The data table also includes sample use.
- This subject consent data table contains a subject ID, consent group information, and affection status for a single WHIM patient.
- This sample attributes data table includes body site where sample was collected, analyte type, tumor status, and sequencing center.
- This subject phenotype data table contains disease onset age, height at enrollment, birthplace, sex, race, CXCR4 status, age, and presence of clinical characteristics of WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis).
C0680251 (UMLS CUI [1,2])
C0343642 (UMLS CUI [1,2])
C0086438 (UMLS CUI [1,3])
C0239998 (UMLS CUI [1,4])
C0027947 (UMLS CUI [1,5])
C1332823 (UMLS CUI [1,6])
C0026882 (UMLS CUI [1,7])
C0549184 (UMLS CUI [1,2])