A novel frameshift mutation in FGA (c.1846 del A) leading to congenital afibrinogenemia in a consanguineous Syrian family.
Congenital afibrinogenemia is a rare autosomal recessive coagulation disorder characterized essentially by bleeding symptoms, but miscarriages and, paradoxically, thromboembolic events can also occur. Most reported mutations leading to congenital afibrinogenemia are located in FGA encoding the fibrinogen A α-chain. In this study, we analysed 12 individuals from a consanguineous Syrian family with reduced or absent fibrinogen levels: those with fibrinogen levels around 1 g/l (n = 7) were found to be heterozygous for a novel frameshift mutation in FGA exon 5 (c.1846 del A) and those with undetectable fibrinogen levels (n = 5) were homozygous for the same mutation. This novel frameshift mutation is the most C-terminal causative FGA mutation identified to date in afibrinogenemic patients. The resulting aberrant Aα-chain (p.Thr616HisfsX32) is most likely synthesized, but is less efficiently assembled and/or secreted into the circulation given the phenotype of asymptomatic hypofibrinogenemia in heterozygous individuals and bleeding diathesis in homozygous individuals.
Division of Angiology and Haemostasis, University Hospital, Geneva, Switzerland.
Emmanuel
E
Levrat
Imad
I
Aboukhamis
Philippe
P
de Moerloose
Jaafar
J
Farho
Sahar
S
Chamaa
Guido
G
Reber
Alexandre
A
Fort
Marguerite
M
Neerman-Arbez
D000328:Adult; D000347:Afibrinogenemia / Q000151:congenital / Q000235:genetics / Q000503:physiopathology; D003241:Consanguinity; D004198:Disease Susceptibility; D005091:Exons; D005260:Female; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D006470:Hemorrhage; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype; D013593:Syria
C464794:fibrinogen Aalpha; D005340:Fibrinogen