Maternal chromosome 4 heterodisomy/isodisomy and Bβ chain Trp323X mutation resulting in severe hypodysfibrinogenaemia

Qiulan Ding; Qi Ouyang; Xiaodong Xi; Xuefeng Wang; Yiping Shen; Hongli Wang

doi:10.1160/TH12-02-0088

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(04): 654-661
DOI: 10.1160/TH12-02-0088

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Maternal chromosome 4 heterodisomy/isodisomy and Bβ chain Trp323X mutation resulting in severe hypodysfibrinogenaemia

Qiulan Ding

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Qi Ouyang

²State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China

³Department of Laboratory Medicine, Eye & ENT Hospital affiliated to Fudan University, Shanghai, China

,

Xiaodong Xi

²State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China

,

Xuefeng Wang

¹Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

,

Yiping Shen

⁴Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

⁵Department of Laboratory Medicine, Children's Hospital, Boston , Massachusetts, USA

,

Hongli Wang

²State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China

› Author Affiliations

Abstract

Summary

We report a rare case of congenital hypodysfibrinogenaemia due to maternal uniparental disomy of chromosome 4 (mat UPD 4) and a maternally inherited novel nonsense mutation Trp323X in the fibrinogen Bβ chain (FGB) gene. Western blot analysis of patient's plasma revealed an abnormal fibrinogen which consisted of truncated Bβ chain and normal Aα and γ chains. Patient's clinical history and laboratory evidence are presented. Microsatellite genotyping analysis revealed a mixed nature of heterodisomy and isodisomy along chromosome 4. High density SNP genotyping array analysis further confirmed the mat UPD 4 and defined two segments of chromosome 4 (4pter-p15.33 and 4q31.21–4q32.3) as maternal isodisomy (iUPD4) and the remaining regions as maternal heterodisomy (hUPD4), with the FGB gene carrying the mutation resided in the iUPD4 region on the long (q) arm. It was predicted that the segmental nature of iUPD and hUPD was caused by three recombination events at positions around 167.96 cM, 145.51 cM and 14.40 cM on chromosome 4 followed by a meiosis I non-disjunction. This case is clinically and molecularly unique and offers an opportunity for understanding novel mechanisms of congenital hypodysfibrinogenaemia associated with complex UPD and fibrinogen secretion.

Keywords

Fibrinogen / fibrin - haemostasis - gene mutations - thrombosis

Full Text

References

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