Identification of novel mutations in patients with fibrinogen disorders and genotype/phenotype correlations

Elena Chinni, Giovanni Tiscia, Giovanni Favuzzi, Filomena Cappucci, Giuseppe Malcangi, Rossana Bagna, Claudia Izzi, Domenica Rizzi, Valerio De Stefano, Elvira Grandone

Research output: Contribution to journalArticle

Abstract

Background. Congenital fibrinogen disorders are caused by variants occurring within the fibrinogen gene cluster. We describe ten subjects with disease-causative variants, adding information on such disorders. Materials and methods. Ten subjects were referred to our Centre because of likely hypo/ dysfibrinogenaemia. We evaluated the function and quantity of fibrinogen, using Clauss and immunoreactive assays, and performed genetic investigations by direct sequencing of alpha, beta and gamma chain-encoding genes. Mutations were analysed using SIFT and Polyphen-2 algorithms. Results. We identified one afibrinogenaemic patient (alpha p.Arg178∗Homozygote) with bleeding/ thrombotic events, three heterozygous patients with hypo/dysfibrinogenaemia (gamma p.Thr47ILeu combined with beta IVS7+1G>T; beta p.Cys95Ser; beta p.Arg196Cys) referred for bleeding or thrombotic episodes and six heterozygous subjects with hypofibrinogenaemia (alpha p.Glu41Lys; gamma p.Gly191Val; beta p.Gly288Ser; gamma p.His333Arg; gamma p.Asp342Glu and p.343-344 duplication; gamma p.Asp356Val), of whom four were symptomatic. Five novel missense changes and one novel duplication variant were found, all in hypofibrinogenaemic subjects: P.Glu41Lys (SIFT score 0, Polyphen-2 score 0.986) was identified in a woman with bleeding after major orthopaedic surgery; p.Gly191Val (SIFT score 0.02, Polyphen-2 score 1) in an asymptomatic woman; p.His333Arg (SIFT score 0, Polyphen-2 score 1) in a woman with a post-partum haemorrhage; and p.Asp342Glu (SIFT score 0.23, Polyphen-2 score 0.931); and an Asn-343 and Asp-344 duplication in a child who developed a haematoma following a fall. Discussion. All but one of the novel mutations were in symptomatic subjects and are predicted to be deleterious. Our findings shed more light on genotype-phenotype relationships in congenital fibrinogen disorders.

Original languageEnglish
Pages (from-to)247-254
Number of pages8
JournalBlood Transfusion
Volume17
Issue number3
DOIs
Publication statusPublished - Jan 1 2019

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Genetic Association Studies
Fibrinogen
Hemorrhage
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Mutation
Multigene Family
Hematoma
Orthopedics
Genotype
Phenotype
Genes

Keywords

  • Fibrinogen
  • Genotype
  • Phenotype

ASJC Scopus subject areas

  • Immunology and Allergy
  • Hematology

Cite this

Identification of novel mutations in patients with fibrinogen disorders and genotype/phenotype correlations. / Chinni, Elena; Tiscia, Giovanni; Favuzzi, Giovanni; Cappucci, Filomena; Malcangi, Giuseppe; Bagna, Rossana; Izzi, Claudia; Rizzi, Domenica; De Stefano, Valerio; Grandone, Elvira.

In: Blood Transfusion, Vol. 17, No. 3, 01.01.2019, p. 247-254.

Research output: Contribution to journalArticle

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AU - Tiscia, Giovanni

AU - Favuzzi, Giovanni

AU - Cappucci, Filomena

AU - Malcangi, Giuseppe

AU - Bagna, Rossana

AU - Izzi, Claudia

AU - Rizzi, Domenica

AU - De Stefano, Valerio

AU - Grandone, Elvira

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N2 - Background. Congenital fibrinogen disorders are caused by variants occurring within the fibrinogen gene cluster. We describe ten subjects with disease-causative variants, adding information on such disorders. Materials and methods. Ten subjects were referred to our Centre because of likely hypo/ dysfibrinogenaemia. We evaluated the function and quantity of fibrinogen, using Clauss and immunoreactive assays, and performed genetic investigations by direct sequencing of alpha, beta and gamma chain-encoding genes. Mutations were analysed using SIFT and Polyphen-2 algorithms. Results. We identified one afibrinogenaemic patient (alpha p.Arg178∗Homozygote) with bleeding/ thrombotic events, three heterozygous patients with hypo/dysfibrinogenaemia (gamma p.Thr47ILeu combined with beta IVS7+1G>T; beta p.Cys95Ser; beta p.Arg196Cys) referred for bleeding or thrombotic episodes and six heterozygous subjects with hypofibrinogenaemia (alpha p.Glu41Lys; gamma p.Gly191Val; beta p.Gly288Ser; gamma p.His333Arg; gamma p.Asp342Glu and p.343-344 duplication; gamma p.Asp356Val), of whom four were symptomatic. Five novel missense changes and one novel duplication variant were found, all in hypofibrinogenaemic subjects: P.Glu41Lys (SIFT score 0, Polyphen-2 score 0.986) was identified in a woman with bleeding after major orthopaedic surgery; p.Gly191Val (SIFT score 0.02, Polyphen-2 score 1) in an asymptomatic woman; p.His333Arg (SIFT score 0, Polyphen-2 score 1) in a woman with a post-partum haemorrhage; and p.Asp342Glu (SIFT score 0.23, Polyphen-2 score 0.931); and an Asn-343 and Asp-344 duplication in a child who developed a haematoma following a fall. Discussion. All but one of the novel mutations were in symptomatic subjects and are predicted to be deleterious. Our findings shed more light on genotype-phenotype relationships in congenital fibrinogen disorders.

AB - Background. Congenital fibrinogen disorders are caused by variants occurring within the fibrinogen gene cluster. We describe ten subjects with disease-causative variants, adding information on such disorders. Materials and methods. Ten subjects were referred to our Centre because of likely hypo/ dysfibrinogenaemia. We evaluated the function and quantity of fibrinogen, using Clauss and immunoreactive assays, and performed genetic investigations by direct sequencing of alpha, beta and gamma chain-encoding genes. Mutations were analysed using SIFT and Polyphen-2 algorithms. Results. We identified one afibrinogenaemic patient (alpha p.Arg178∗Homozygote) with bleeding/ thrombotic events, three heterozygous patients with hypo/dysfibrinogenaemia (gamma p.Thr47ILeu combined with beta IVS7+1G>T; beta p.Cys95Ser; beta p.Arg196Cys) referred for bleeding or thrombotic episodes and six heterozygous subjects with hypofibrinogenaemia (alpha p.Glu41Lys; gamma p.Gly191Val; beta p.Gly288Ser; gamma p.His333Arg; gamma p.Asp342Glu and p.343-344 duplication; gamma p.Asp356Val), of whom four were symptomatic. Five novel missense changes and one novel duplication variant were found, all in hypofibrinogenaemic subjects: P.Glu41Lys (SIFT score 0, Polyphen-2 score 0.986) was identified in a woman with bleeding after major orthopaedic surgery; p.Gly191Val (SIFT score 0.02, Polyphen-2 score 1) in an asymptomatic woman; p.His333Arg (SIFT score 0, Polyphen-2 score 1) in a woman with a post-partum haemorrhage; and p.Asp342Glu (SIFT score 0.23, Polyphen-2 score 0.931); and an Asn-343 and Asp-344 duplication in a child who developed a haematoma following a fall. Discussion. All but one of the novel mutations were in symptomatic subjects and are predicted to be deleterious. Our findings shed more light on genotype-phenotype relationships in congenital fibrinogen disorders.

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