Congenital afibrinogenaemia caused by uniparental isodisomy of chromosome 4 containing a novel 15-kb deletion involving fibrinogen Aα-chain gene

Silvia Spena, Stefano Duga, Rosanna Asselta, Flora Peyvandi, Chularatana Mahasandana, Massimo Malcovati, Maria Luisa Tenchini

Research output: Contribution to journalArticlepeer-review

Abstract

Among rare inherited deficiencies of coagulation factors, congenital afibrinogenaemia is characterised by the lack of fibrinogen in plasma. In the last few years, several genetic defects underlying afibrinogenaemia (mostly point mutations) have been described in the fibrinogen gene cluster. In this study, the molecular basis responsible for afibrinogenaemia in a Thai proband was defined. Point mutation screening was accomplished by directly sequencing the three fibrinogen genes. The impossibility to amplify fibrinogen Aα-chain gene (FGA) exons 5 and 6 suggested the presence of a homozygous deletion. A specific long-range PCR assay enabled the identification of a novel 15-kb deletion, representing the largest afibrinogenaemia-causing deletion described so far. Direct sequencing of the deletion junction allowed mapping of the breakpoints in FGA intron 4 and in the intergenic region between Aα- and Bβ-chain genes. Since the mutation was inherited only from the mother and nonpaternity was ruled out, a maternal uniparental disomy (UPD) was hypothesised. UPD test, carried out with markers covering the whole chromosome 4, revealed that maternal isodisomy was responsible for homozygosity of the 15-kb deletion in the proband. The apparently normal phenotype of the proband, except for afibrinogenaemia, suggests that UPD for chromosome 4 is clinically silent. This represents the first case of a documented complete isodisomy of chromosome 4 causing the phenotypic expression of a recessive disorder. In silico analyses of the regions surrounding the breakpoints suggested that the 15-kb deletion might have originated from an inappropriate repair of a double-strand break by the nonhomologous end joining mechanism.

Original languageEnglish
Pages (from-to)891-898
Number of pages8
JournalEuropean Journal of Human Genetics
Volume12
Issue number11
DOIs
Publication statusPublished - Nov 2004

Keywords

  • Chromosome 4
  • Congenital afibrogenaemia
  • FGA
  • Fibronigen cluster
  • Large deletion
  • Short direct repeats
  • UPD

ASJC Scopus subject areas

  • Genetics(clinical)

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