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

2.50
Hdl Handle:
http://hdl.handle.net/10547/595147
Title:
Haemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivation
Authors:
Janczar, Szymon; Kosinska, Joanna; Ploski, Rafal; Pastorczak, Agata; Wegner, Olga; Zalewska-Szewczyk, Beata; Paige, Adam J.W.; Borowiec, Maciej; Mlynarski, Wojciech
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.
Affiliation:
Medical University of Lodz; Warsaw Medical University; University of Bedfordshire
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
Issue Date:
Jan-2016
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
Appears in Collections:
Biomedical Science

Full metadata record

DC FieldValue Language
dc.contributor.authorJanczar, Szymonen
dc.contributor.authorKosinska, Joannaen
dc.contributor.authorPloski, Rafalen
dc.contributor.authorPastorczak, Agataen
dc.contributor.authorWegner, Olgaen
dc.contributor.authorZalewska-Szewczyk, Beataen
dc.contributor.authorPaige, Adam J.W.en
dc.contributor.authorBorowiec, Maciejen
dc.contributor.authorMlynarski, Wojciechen
dc.date.accessioned2016-01-28T11:19:45Zen
dc.date.available2016-01-28T11:19:45Zen
dc.date.issued2016-01en
dc.identifier.citationJanczar, 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):43-7en
dc.identifier.issn1878-0849en
dc.identifier.pmid26691666en
dc.identifier.doi10.1016/j.ejmg.2015.12.004en
dc.identifier.urihttp://hdl.handle.net/10547/595147en
dc.description.abstractWe 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.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S1769721215300598en
dc.rightsArchived with thanks to European journal of medical geneticsen
dc.subjectmoyamoyaen
dc.subjecthaemophilia Aen
dc.subjectaortic coarctationen
dc.subjecthypertensionen
dc.subjectarrhythmiasen
dc.subjectX chromosome inactivationen
dc.titleHaemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivationen
dc.typeArticleen
dc.contributor.departmentMedical University of Lodzen
dc.contributor.departmentWarsaw Medical Universityen
dc.contributor.departmentUniversity of Bedfordshireen
dc.identifier.journalEuropean journal of medical geneticsen

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