Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(08): 1478-1485
DOI: 10.1160/TH17-01-0046

Coagulation and Fibrinolysis

Schattauer GmbH

Complex recombination with deletion in the F8 and duplication in the TMLHE mediated by int22h copies during early embryogenesis

Changming Chen

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

,

Xiaoling Xie

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

,

Xi Wu

²Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Yeling Lu

²Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Xuefeng Wang

²Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Wenman Wu

²Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Yiqun Hu

³Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Qiulan Ding

²Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

› Author Affiliations

Summary

Haemophilia A (HA) is a common X-linked recessive bleeding disorder and almost one half of patients with severe HA are caused by intron 22 inversion (Inv22) in the F8. Inv22 is considered to be almost exclusively of meiotic origin in germ cells during spermatogenesis and only one mosaic Inv22 female carrier with the mutation possibly occurring during mitosis of the embryo has been reported so far. Previously we have identified a novel complex recombination mediated by int22h copies in a sporadic severe HA pedigree and herein we have localised the sequences flanking the breakpoint region using genome walking technique, AccuCopy technique, gene chip and real-time PCR. The disease causing genetic variant registered an 18.1 kb deletion including part of int22h-1 through the intron 23 of F8 and a 113.3 kb duplication of part of int22h-2 through the intron 1 of TMLHE inserted in the religated region of the F8. Two intrinsically linked mechanisms of recombination-dependent DNA replication: microhomology-mediated break-induced replication (MMBIR) followed by break-induced replication (BIR) might be responsible for the incident of the complex recombination during early embryogenesis of the proband’s mother.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Keywords

Haemophilia A - intron 22 inversion - somatic and germline mosaicism - genomic recombination

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Supplementary Material

Supplementary Material

Online Supplementary Material (PDF)