Aims The frequency of X chromosome pericentric inversion is much less than that of autosome chromosome. We hereby characterise a pericentric inversion of X chromosome associated with severe factor VIII (FVIII) deficiency in a sporadic haemophilia A (HA) pedigree.
Methods PCR primer walking and genome walking strategies were adopted to identify the exact breakpoints of the inversion. Copy number variations (CNVs) of the F8 and the whole chromosomes were detected by AccuCopy and Affymetrix CytoScan High Definition (HD) assays, respectively. A karyotype analysis was performed by cytogenetic G banding technique.
Results We identified a previously undescribed type of pericentric inversion of the X chromosome [inv(X)(p11.21q28)] in the proband with FVIII:C <1%. One breakpoint was located in the intron 7 of the F8, which disrupted the transcription of the F8, and the other located in the upstream of the PFKFB1 of the X chromosome. The inversion segment was approximately 64.4% of the total chromosomal length. The karyotype analysis of the X chromosome confirmed the pericentric inversion of the X chromosome in the proband and his mother. A haplotype analysis traced the inversion to his maternal grandfather, who was not a somatic mosaic of the inversion. This finding indicated that the causative mutation may originate from his germ cells or a rare possibility of germ-cell mosaicism.
Conclusions The characterisation of pericentric inversion involving F8 extended the molecular mechanisms causing HA. The pericentric inversion rearrangement involves F8 by non-homologous end joining is responsible for pathogensis of severe HA.
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YX and JZ contributed equally to this work, and should be considered as co-first authors.
Handling editor Mary Frances McMullin
Contributors YX, JZ, QD, CC, X Wu, Xuefeng W, HW and XJ designed the experiments. YX, JZ, CC and X Wu performed the experiments and analysed the data. YX, JZ and QD wrote the manuscript. Xuefeng W, HW and XJ supervised the study. All authors discussed the results and reviewed the manuscript.
Funding The General Program of National Natural Science Foundation of China (81300396), Shanghai Sanitary Bureau Researcher Program (2012308), The National Basic Research Program of China (2013CB966800).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics Committee of Ruijin Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
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