Xin Yu, Zhou Jingyi, Ding Qiulan, Chen Changming, Wu Xi, Wang Xuefeng, Wang Hongli, Jiang Xiaofeng
Department of Laboratory Medicine, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Clin Pathol. 2017 Aug;70(8):656-661. doi: 10.1136/jclinpath-2016-204050. Epub 2017 Jan 10.
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.
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.
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.
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.
X染色体臂间倒位的频率远低于常染色体。在此，我们对一个散发性A型血友病（HA）家系中与严重因子VIII（FVIII）缺乏相关的X染色体臂间倒位进行了特征描述。
采用PCR引物步移和基因组步移策略来确定倒位的确切断点。分别通过AccuCopy和Affymetrix CytoScan高分辨率（HD）检测法检测因子VIII基因和全染色体的拷贝数变异（CNV）。采用细胞遗传学G带技术进行核型分析。
我们在FVIII:C<1%的先证者中鉴定出一种先前未描述的X染色体臂间倒位类型[inv(X)(p11.21q28)]。一个断点位于因子VIII基因第7内含子，破坏了该基因的转录，另一个断点位于X染色体因子VIII基因上游。倒位片段约占染色体总长度的64.4%。对X染色体的核型分析证实了先证者及其母亲存在X染色体臂间倒位。单倍型分析将该倒位追溯至其外祖父，外祖父并非该倒位的体细胞嵌合体。这一发现表明致病突变可能源于其生殖细胞，或者存在生殖细胞嵌合的罕见可能性。
涉及因子VIII基因的臂间倒位特征扩展了导致A型血友病的分子机制。通过非同源末端连接的臂间倒位重排是严重A型血友病发病的原因。
