Combined de-novo mutation and non-random X-chromosome inactivation causing Wiskott-Aldrich syndrome in a female with thrombocytopenia

J Clin Immunol. 2013 Oct;33(7):1150-5. doi: 10.1007/s10875-013-9927-9. Epub 2013 Aug 14.

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody Formation / genetics
  • DNA Methylation / genetics
  • Female
  • Genes, X-Linked / genetics
  • Genotype
  • Humans
  • Immunity / genetics
  • Infant
  • Infant, Newborn
  • Microarray Analysis
  • Mutation / genetics
  • Pedigree
  • Polymorphism, Single Nucleotide
  • T-Lymphocytes / immunology*
  • Thrombocytopenia / diagnosis*
  • Thrombocytopenia / genetics
  • Wiskott-Aldrich Syndrome / diagnosis*
  • Wiskott-Aldrich Syndrome / genetics
  • Wiskott-Aldrich Syndrome Protein Family / genetics
  • Wiskott-Aldrich Syndrome Protein Family / metabolism*

Substances

  • Wiskott-Aldrich Syndrome Protein Family