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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.

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