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Scientific article
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English

A homozygous duplication of the FGG exon 8-intron 8 junction causes congenital afibrinogenemia. Lessons learned from the study of a large consanguineous Turkish family

Published inHaematologica, vol. 107, no. 5, p. 1064-1071
Publication date2022-05
First online date2021
Abstract

Congenital afibrinogenemia is the most severe congenital fibrinogen disorder, characterized by undetectable fibrinogen in circulation. Causative mutations can be divided into two main classes: null mutations with no protein production at all and missense mutations producing abnormal protein chains that are retained inside the cell. The vast majority of cases are due to single base pair mutations or small insertions or deletions in the coding regions or intron-exon junctions of FGB, FGA and FGG. Only a few large rearrangements have been described, all deletions involving FGA. Here we report the characterization of a 403 bp duplication of the FGG exon 8-intron 8 junction accounting for congenital afibrinogenemia in a large consanguineous family from Turkey. This mutation, which had escaped detection by Sanger sequencing of short polymerase chain reaction (PCR) amplicons of coding sequences and splice sites, was identified by studying multiple alignments of reads obtained from whole exome sequencing of a heterozygous individual followed by PCR amplification and sequencing of a larger portion of FGG. Because the mutation duplicates the donor splice site of intron 8, we predicted that the impact of the mutation would be on FGG transcript splicing. Analysis of mRNA produced by cells transiently transfected with normal or mutant minigene constructs showed that the duplication causes production of several aberrant FGG transcripts generating premature truncating codons.

eng
Keywords
  • Afibrinogenemia / genetics
  • Consanguinity
  • Exons
  • Fibrinogen
  • Humans
  • Introns
  • Mutation
  • Turkey
Citation (ISO format)
GUIPPONI, Michel et al. A homozygous duplication of the <i>FGG </i>exon 8-intron 8 junction causes congenital afibrinogenemia. Lessons learned from the study of a large consanguineous Turkish family. In: Haematologica, 2022, vol. 107, n° 5, p. 1064–1071. doi: 10.3324/haematol.2021.278945
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Article (Accepted version)
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Identifiers
ISSN of the journal0390-6078
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