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Combined De-Novo Mutation and Non-Random X-Chromosome Inactivation Causing Wiskott-Aldrich Syndrome in a Female with Thrombocytopenia

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Abstract

Objective

Disorders linked to mutations in the X chromosomes typically affect males. The aim of the study is to decipher the mechanism of disease expression in a female patient with a heterozygous mutation on the X-chromosome.

Patients and Methods

Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Genomic ribonucleic acid (DNA) and complementary DNA (cDNA) underwent Sanger sequencing. Protein analysis was performed by flow cytometry. X-inactivation patterns were analyzed by evaluating the DNA methylation status and cDNA clonal expression of several genes on the X-chromosome. SNP array was used for molecular karyotyping of the X-chromosome.

Results

A female with thrombocytopenia, eczema and mild T-lymphocyte abnormalities with extensive negative diagnostic testing, was suspected to have Wiskott-Aldrich syndrome (WAS)/X-linked thrombocytopenia. Although the girl had a mutation (c.397G > A, p.E133K) in only one allele, she was found to have an extremely skewed X-inactivation pattern and no expression of the WAS protein. Family studies using DNA methylation analysis and cDNA clonal expression of several genes on the X-chromosome demonstrated that the patient developed de-novo non-random inactivation of the X-chromosome that does not carry the mutation. Genome-wide high-density molecular karyotyping excluded deletions and amplifications as a cause for the non-random inactivation of one X-chromosome.

Conclusions

Our study emphasizes the need to test selected female patients with complete or incomplete disease expression for X-linked disorders even in the absence of a family history.

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Financial Disclosure

The authors acknowledge the support to this work from the C17 Council and the support they receive from Childhood Cancer Canada, and Coast to Coast Against Cancer Foundation, the Nicola’s Kids Triathlon and Canadian Institute for Health Research (funding reference 102528).

Conflict of Interest

The authors have no conflicts of interest relevant to this article to disclose.

Author information

Authors and Affiliations

  1. Genetics and Genome Biology Program, Research Institute, University of Toronto, Toronto, Ontario, Canada

    Boonchai Boonyawat, Santhosh Dhanraj, Bozana Zlateska, Stephen Meyn, Stephen W. Scherer & Yigal Dror

  2. The Division of Haematology/Oncology, University of Toronto, Toronto, Ontario, Canada

    Boonchai Boonyawat, Fahad al Abbas, Victor Blanchette & Yigal Dror

  3. Division of Immunology, University of Toronto, Toronto, Ontario, Canada

    Eyal Grunenbaum & Chaim M. Roifman

  4. Molecular Genetic Laboratory, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Leslie Steele

  5. Hematology Division, University of Utah, Salt Lake City, UT, USA

    Sabina Swierczek & Josef Prchal

  6. Seattle Children’s Research Institute, University of Washington, Seattle, WA, USA

    Qili Zhu, Troy R. Torgerson & Hans D. Ochs

  7. Division of Hematology Oncology, SickKids Hospital, 555 University Avenue, Toronto, Ontario, M5G1X8, Canada

    Yigal Dror

Authors
  1. Boonchai Boonyawat
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  2. Santhosh Dhanraj
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  4. Bozana Zlateska
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  7. Leslie Steele
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  8. Stephen Meyn
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  11. Sabina Swierczek
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  13. Qili Zhu
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  15. Hans D. Ochs
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  16. Yigal Dror
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Corresponding author

Correspondence to Yigal Dror.

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Contributor’s Statement

BB designed and performed experiments, analyzed data, wrote the manuscript; SD designed and performed experiments, analyzed data, wrote the manuscript; FAA design laboratory investigation; BZ analyzed data, wrote the manuscript; EG performed experiments, analyzed data, wrote the manuscript; CMR designed experiments; LS designed and performed experiments; SM design laboratory investigation, data interpretation; VB design laboratory investigation, SWS provided control data and technical support, SS performed experiments, JP designed experiments, QZ designed experiments, TRT designed experiments, HDO, designed experiments, analyzed data, wrote the manuscript; YD conceived and designed research, analyzed data and wrote the paper.

Boonchai Boonyawat and Santhosh Dhanraj contributed equally to the work.

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Boonyawat, B., Dhanraj, S., al Abbas, F. et al. Combined De-Novo Mutation and Non-Random X-Chromosome Inactivation Causing Wiskott-Aldrich Syndrome in a Female with Thrombocytopenia. J Clin Immunol 33, 1150–1155 (2013). https://doi.org/10.1007/s10875-013-9927-9

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  • DOI: https://doi.org/10.1007/s10875-013-9927-9

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