title: Haemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivation.
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.
authors.affiliation: Department of Paediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Janczar
authors.affiliation: Department of Medical Genetics, Warsaw Medical University, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kosinska
authors.affiliation: Department of Medical Genetics, Warsaw Medical University, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
authors.affiliation: Department of Paediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Pastorczak
authors.affiliation: Department of Paediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland.
authors.forename: Olga
authors.initials: O
authors.lastname: Wegner
authors.affiliation: Department of Paediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Zalewska-Szewczyk
authors.affiliation: Department of Life Science, University of Bedfordshire, UK.
authors.forename: Adam J W
authors.initials: AJ
authors.lastname: Paige
authors.affiliation: Department of Paediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Borowiec
authors.affiliation: Department of Paediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Poland. Electronic address: wojciech.mlynarski@umed.lodz.pl.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Mlynarski
mesh_terms: D000293:Adolescent; D000072017:Deubiquitinating Enzymes; D044127:Epigenesis, Genetic; D005260:Female; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D009072:Moyamoya Disease / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: D008565:Membrane Proteins; C518017:BRCC3 protein, human; D000072017:Deubiquitinating Enzymes
keywords: Aortic coarctation; Arrhythmias; Haemophilia A; Hypertension; Moyamoya; X chromosome inactivation