Identification of eight novel mutations and one reccurent mutation in F13B gene leading to inherited, heterozygous FXIII deficiency
V. Ivaskevicius1, A. Biswas1, S. Singh1, G. Kappert2, S. Halimeh2, H. Rott2, S. Flommersfeld3, H. Trobisch2, U. Kreibich4, M. Olivieri5, J. Oldenburg1 (1Bonn, Germany, 2Duisburg, Germany, 3Marburg, Germany, 4Zwickau, Germany, 5Munich, Germany)
Bleeding Disorders - Clinical Studies
Time: 08:30 - 09:45
Objective: Inherited severe factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder usually caused by mutations in the F13A1 gene (very rarely in F13B gene) and affecting approximately one in 1–3 million people. On the other hand the heterozygous (only one affected allele) FXIII deficiency is expected to be more common affecting approximately one out of 1000 inhabitants with a reduction of FXIII activity by 50% in most cases. Nevertheless, heterozygous FXIII deficiency belongs to one of the most underdiagnosed bleeding disorders so far. This is, because most patients do not develop bleeding complications in daily life.
Methods: In this work we report the results of the occurrence of F13B gene mutations among the German patients with mild (FXIII activity <65% of normal) FXIII deficiency. Genomic DNA of the patients has been analyzed routinely by direct sequencing between 2009 and 2015. In total, 13 of more than 200 patients with reduced FXIII levels and suspected inherited, heterozygous deficiency had demonstrated mutations in F13B gene.
Results: Eight novel and one reccurent F13B gene mutations have been identified. All persons were heterozygous for one mutation. The majority of patients (10/13) carried missense mutations, while the remaining three patients showed distinct genetic defects reaveraling one novel small deletion (c.1958delT), one novel small insertion (c.365insA) and one novel splice site (IVS5-1G>A) mutation in intron 5. Among six different missense mutations, five were novel (p.Phe42Val, p.Tyr163His, p.Cys213Trp, p.Val266Pro, p.Ala416Glu) affecting highly conserved regions of the FXIII-B Subunit. In vitro studies of the novel missense mutations have been recently initiated. The remaining previuosly described missense mutation in the 6th Sushi domain (pCys336Phe) was surprisingly found in 5 of 13 analysed patients. No mutations have been detected in F13A1 gene.
Conclusion: i) Eight novel, potentially causative mutations have been identified within F13B gene, ii) p.Cys336Phe mutation seems to be common in German population, iii) F13B mutations leading to FXIII (B-Subunit) deficiency may not be as rare as reported in the literature.