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.

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Authors

Elena Chinni - Atherosclerosis and Thrombosis Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (Foggia)

Giovanni Tiscia - Atherosclerosis and Thrombosis Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (Foggia)

Giovanni Favuzzi - Atherosclerosis and Thrombosis Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (Foggia)

Filomena Cappucci - Atherosclerosis and Thrombosis Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (Foggia)

Giuseppe Malcangi - Department of Interdisciplinary Medicine, University of Bari, Bari

Rossana Bagna - Neonatology and Neonatal Intensive Care Unit, University Hospital, "Città della Salute e della Scienza", Turin

Claudia Izzi - Department of Obstetrics and Gynaecology, University of Brescia, Brescia

Domenica Rizzi - Department of Paediatric and Neonatal Pathology, Marche Nord Hospital, Pesaro

Valerio De Stefano - Institute of Haematology, Catholic University, Rome, Italy

Elvira Grandone - Atherosclerosis and Thrombosis Unit, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo (Foggia)

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