A pericentric inversion of chromosome X disrupting and resulting in haemophilia A.

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 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 8, which disrupted the transcription of the and the other located in the upstream of the 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 extended the molecular mechanisms causing HA. The pericentric inversion rearrangement involves by non-homologous end joining is responsible for pathogensis of severe HA.