Factor XI gene variants in factor XI-deficient patients of Southern Italy

identification of a novel mutation and genotype-phenotype relationship

Giovanni L Tiscia, Giovanni Favuzzi, Maria R Lupone, Filomena Cappucci, Michele Schiavulli, Valentina Mirabelli, Giovanna D'Andrea, Elena Chinni, Nicola Giuliani, Rocco Caliandro, Elvira Grandone

Research output: Contribution to journalArticle

Abstract

Congenital Factor XI (FXI) deficiency shows a high variability in clinical phenotype. To date, many allele variants have been shown to cause this bleeding disorder. However, the genotype-phenotype relationship is difficult to establish. This report provides insights into this bleeding disorder. Sixteen unrelated Italian index cases with congenital FXI deficiency and their relatives were investigated. After the identification of the deficiency, we obtained DNA from each subject and analyzed the FXI gene using direct sequencing. We identified 5 and 11 individuals with severe and moderate deficiency of FXI activity, respectively. Most patients (8/16) carried mutations in the Apple 2 domain and 4 patients showed c.403G>T (p.Glu135*; type II mutation). Four novel compound heterozygosities were identified. Bleeding symptoms were present in two severely deficient subjects carrying the combinations c.901T>C (p.Phe301Leu)/c.1556G>A (p.Trp519*) and c.943G>A (p.Glu315)/c.1556G>A (p.Trp519*), respectively. Bleeding episodes were also observed in the presence of a moderate deficiency in two individuals heterozygous for c.449C>T (p.Thr150Met) and c.1253G>T (p.Gly418Val), respectively. One novel mutation, c.1682C>A (p.Ala561Asp), was identified as potentially deleterious in an asymptomatic individual. We confirm an unclear prediction of phenotype from mutational data. The FXI levels should be coupled with FXI analysis for a more comprehensive prediction of the bleeding phenotype in FXI deficiency.

Original languageEnglish
Pages (from-to)17043
JournalHuman Genome Variation
Volume4
DOIs
Publication statusPublished - 2017

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Factor XI
Factor XI Deficiency
Italy
Genes
Genotype
Hemorrhage
Phenotype
Mutation
Malus
Statistical Factor Analysis
Factor analysis
Alleles
DNA

Keywords

  • Journal Article

Cite this

Factor XI gene variants in factor XI-deficient patients of Southern Italy : identification of a novel mutation and genotype-phenotype relationship. / Tiscia, Giovanni L; Favuzzi, Giovanni; Lupone, Maria R; Cappucci, Filomena; Schiavulli, Michele; Mirabelli, Valentina; D'Andrea, Giovanna; Chinni, Elena; Giuliani, Nicola; Caliandro, Rocco; Grandone, Elvira.

In: Human Genome Variation, Vol. 4, 2017, p. 17043.

Research output: Contribution to journalArticle

Tiscia, Giovanni L ; Favuzzi, Giovanni ; Lupone, Maria R ; Cappucci, Filomena ; Schiavulli, Michele ; Mirabelli, Valentina ; D'Andrea, Giovanna ; Chinni, Elena ; Giuliani, Nicola ; Caliandro, Rocco ; Grandone, Elvira. / Factor XI gene variants in factor XI-deficient patients of Southern Italy : identification of a novel mutation and genotype-phenotype relationship. In: Human Genome Variation. 2017 ; Vol. 4. pp. 17043.
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abstract = "Congenital Factor XI (FXI) deficiency shows a high variability in clinical phenotype. To date, many allele variants have been shown to cause this bleeding disorder. However, the genotype-phenotype relationship is difficult to establish. This report provides insights into this bleeding disorder. Sixteen unrelated Italian index cases with congenital FXI deficiency and their relatives were investigated. After the identification of the deficiency, we obtained DNA from each subject and analyzed the FXI gene using direct sequencing. We identified 5 and 11 individuals with severe and moderate deficiency of FXI activity, respectively. Most patients (8/16) carried mutations in the Apple 2 domain and 4 patients showed c.403G>T (p.Glu135*; type II mutation). Four novel compound heterozygosities were identified. Bleeding symptoms were present in two severely deficient subjects carrying the combinations c.901T>C (p.Phe301Leu)/c.1556G>A (p.Trp519*) and c.943G>A (p.Glu315)/c.1556G>A (p.Trp519*), respectively. Bleeding episodes were also observed in the presence of a moderate deficiency in two individuals heterozygous for c.449C>T (p.Thr150Met) and c.1253G>T (p.Gly418Val), respectively. One novel mutation, c.1682C>A (p.Ala561Asp), was identified as potentially deleterious in an asymptomatic individual. We confirm an unclear prediction of phenotype from mutational data. The FXI levels should be coupled with FXI analysis for a more comprehensive prediction of the bleeding phenotype in FXI deficiency.",
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