Phenotype and genotype of FXIII deficiency in two unrelated probands: identification of a novel F13A1 large deletion mediated by complex rearrangement

Abstract

Background Inherited Factor XIII deficiency (FXIIID) is one of the most severe and under-diagnosed rare bleeding disorders. Only 5 large deletions involving one or more exons in F13A1 have been reported, and lacking of multiplex ligation-dependent probe amplification (MLPA) assay might underestimate the copy number variations (CNVs) in F13A1 and F13B . We had characterized the clinical presentation of two unrelated severe FXIIID probands and explored the pathogenic mechanisms. Results Both probands experienced several episodes of fatal bleeding and delayed wound healings prior to diagnosis. FXIII activity was measured by the ammonia release assay, and FXIII-A and FXIII-B antigens were determined by ELISA. All the exons including exon-intron boundaries and promoter regions of F13A1 and F13B were amplified and directly sequenced. Copy number variations (CNVs) of F13A1 and F13B were detected by the CNVplex® method. Breakpoints of the F13A1 large deletion were identified by quantitative primer walking combined long-range PCR (LR-PCR) strategies. Proband 1 was found to have compound heterozygous mutations of a novel small deletion (c.1147del) and a missense mutation p.Arg383Ser. Proband 2 was compound heterozygous for a novel large deletion (g.[77815_112815del;112837_116628del]) and a missense mutation p.Arg716Gly in F13A1 . Bioinformatics analysis of the large deletion breakpoints predicted that two fork stalling and template switching and/or microhomology-mediated break-induced replication (FoSTeS/MMBIR) events with two homologies of TCT and C might be responsible for the complex rearrangement. Prophylactic replacement therapy was immediately administered for the two probands upon establishment of the diagnosis. Conclusions We detected two type I FXIIID pedigrees and adopted CNVplex® method to detect CNVs of F13A1 and F13B for the first time. A large heterozygous deletion of g.[77815_112815del;112837_116628del] in F13A1 , mediated by two FoSTeS/MMBIR events, was identified. Electronic supplementary material The online version of this article (10.1186/s13023-019-1144-z) contains supplementary material, which is available to authorized users.

Novel Insights into Heterozygous Factor XIII Deficiency

“…The authors also reported a small deletion in the F13A gene that caused FXIII-A activity, FXIII-A Ag, and FXIII-B Ag of 65.1, 57.6, and 103.1%, respectively, in the heterozygous state. 79 In another study, a large deletion spanning from exon 4 to 11 was detected, causing lower than normal levels and activities of FXIII-A in the heterozygous state. This is the largest F13A gene deletion ever reported.…”

“…In 2019, a severe case of compound heterozygosity was reported, inheriting a large deletion spanning from exon 8 to 9. 79 Her mother, as a heterozygote of this large deletion, had FXIII activity, FXIII-A Ag, and FXIII-B Ag of 55.1, 45.6, and 119.9%, respectively. The authors also reported a small deletion in the F13A gene that caused FXIII-A activity, FXIII-A Ag, and FXIII-B Ag of 65.1, 57.6, and 103.1%, respectively, in the heterozygous state.…”

“…Also we found a significant bleeding among heterozygous individuals; these also were common among healthy individuals, except for miscarriage and impaired wound healing. 6 In the literature review, we found 308 individuals with heterozygous FXIII deficiency, of whom almost all bleeding episodes were due to hemostatic challenges such as trauma, surgery, pregnancy, and childbirth 3 11 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 ( Tables 1 and 2 ).…”

Inherited Factor XIII deficiency: Diagnosis, prevalence and treatment modalities in 2020

“…Il s'agit principalement de mutations faux-sens/non-sens sur le g ene F13A1, et de [194 petites délétions/insertions ainsi que des mutations du site d'épissage. Seules cinq grandes délétions et une duplication de grande taille impliquant un ou plusieurs exons dans le F13A1 ont été identifiés [14].…”

A novel Cys328-terminator mutant implicated in severe coagulation factor XIII deficiency: a case report

“…It has been reported that there are 203 mutations worldwide that have been identified in patients with FXIII deficiency, among which more than 90% are responsible for FXIII A deficiency. In addition to point mutations, there are also small deletions/insertions and even large deletions [ 6 ]. Developments in DNA technology and bioinformatics can help us to understand the structural and functional consequences of the various mutations of FXIII.…”