Identification and characterisation of a novel aberrant pattern of intron 1 inversion with concomitant large insertion and deletion within the F8 gene

Guoling You; Kun Chi; Yeling Lu; Qiulan Ding; Jing Dai; Xiaodong Xi; Hongli Wang; Xuefeng Wang

doi:10.1160/TH13-10-0892

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2014; 112(02): 264-270
DOI: 10.1160/TH13-10-0892

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Identification and characterisation of a novel aberrant pattern of intron 1 inversion with concomitant large insertion and deletion within the F8 gene

Guoling You^a

¹State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine

²Department of Laboratory Medicine, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine

,

Kun Chi^a

¹State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine

,

Yeling Lu

³Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Qiulan Ding

³Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Jing Dai

³Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Xiaodong Xi

¹State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine

,

Hongli Wang

¹State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine

,

Xuefeng Wang

³Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

› Institutsangaben

Abstract

Summary

Intron 1 inversion (Inv1) is a recurrent causative mutation of haemophilia A (HA) and is responsible for 1–5% of severe HA. Inv1 occurs as a result of intra-chromosomal homologous recombination between int1h-1 within intron 1 and int1h-2 located in approximately 125 kb telomeric to the F8 gene. In this report, we presented a previously undescribed aberrant type of Inv1 with complex genomic rearrangement in a pedigree with severe HA. The breakpoints of the rearrangement were identified by the genome walking technique; copy number variations (CNVs) of the F8 gene and X chromosome were detected by AccuCopy technique, Affymetrix CytoScan HD CNV assay and quantitative PCR (qPCR); the F8 transcripts related to the aberrant Inv1 were analysed by reverse transcription PCR (RT-PCR). We have characterised the exact breakpoints of the complex rearrangement, and determined the location and size of the insertion and deletion. The rearrangements can be summarised as an aberrant pattern of Inv1 with a deletion of 2.56 kb and a duplication of 227.3 kb inserted in the rejoining junction within the F8 gene. Our results suggested that this complex genomic rearrangement was generated by two distinct repair mechanisms of fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) and nonallelic homologous recombination (NAHR).

Keywords

Copy number variants - genomic rearrangement - haemophilia A - intron 1 inversion

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Referenzen

References
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