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    Haemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivation

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    Authors
    Janczar, Szymon
    Kosinska, Joanna
    Ploski, Rafal
    Pastorczak, Agata
    Wegner, Olga
    Zalewska-Szewczyk, Beata
    Paige, Adam J.W.
    Borowiec, Maciej
    Mlynarski, Wojciech
    Affiliation
    Medical University of Lodz
    Warsaw Medical University
    University of Bedfordshire
    Issue Date
    2016-01
    Subjects
    moyamoya
    haemophilia A
    aortic coarctation
    hypertension
    arrhythmias
    X chromosome inactivation
    
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    Abstract
    We have recently described a severe haemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and the BRCC3 familial moyamoya gene. The phenotype includes haemophilia A, moyamoya angiopathy, dysmorphia and hypertension. The genetic analysis of the family of our SHAM patient demonstrated carrier state in proband's mother and sister. The patient's mother is apparently well, whereas his currently 18-years-old sister presents with mild haemophilia A, coarctation of the aorta, hypertension, and ventricular arrhythmia. We performed X chromosome inactivation assay based on HpaII methylation analysis of a polymorphic short tandem repeat (STR) in the X linked AR (androgen receptor) gene and used quantitative real-time RT PCR to measure the expression of genes from the deleted region in proband's family members. We found an extremely skewed X chromosome inactivation pattern in the female members of the family leading to preferential inactivation of the X chromosome without Xq28 deletion in patient's sister. We demonstrated differential expression of the genes from the deleted region in four members of the family, that tightly correlates with the clinical features. In conclusion, we show that the haematologic and cardiovascular morbidity and the discrepancy between patient's sister and mother despite the same genetic lesion are due to skewed X chromosome inactivation leading to clinically relevant differential expression of SHAM syndrome genes. This report highlights the role for BRCC3 in cardiovascular physiology and disease, and demonstrates that in some complex hereditary syndromes full diagnostics may require the examination of both genetic and epigenetic events.
    Citation
    Janczar, S. et al (2016) 'Haemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivation'. Eur J Med Genet 59 (1):43-7
    Publisher
    Elsevier
    Journal
    European journal of medical genetics
    URI
    http://hdl.handle.net/10547/595147
    DOI
    10.1016/j.ejmg.2015.12.004
    PubMed ID
    26691666
    Additional Links
    http://www.sciencedirect.com/science/article/pii/S1769721215300598
    Type
    Article
    Language
    en
    ISSN
    1878-0849
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ejmg.2015.12.004
    Scopus Count
    Collections
    Biomedical Science

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