Identification of a third rearrangement at Xq28 that causes severe hemophilia A as a result of homologous recombination between inverted repeats

Pezeshkpoor, Behnaz; Rost, S.; Oldenburg, Johannes; El‐Maarri, Osman

doi:10.1111/j.1538-7836.2012.04809.x

Cited by 19 publications

(29 citation statements)

References 23 publications

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“…1A). Aberrant diagnostic patterns for inv1 have been occasionally described in severe HA, suggesting the possible existence of extra copies of the int1h region, as shown in int22h‐related inversions [6–8]. In order to detect possible quantitative genomic changes, as copy number variations (CNVs), responsible of the unusual results, we applied different technical approaches, such as multiplex ligation‐dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH) and quantitative‐PCR (qPCR) (details available upon request).…”

mentioning

confidence: 99%

Aberrant F8 gene intron 1 inversion with concomitant duplication and deletion in a severe hemophilia A patient from Southern Italy

Sanna

Ceglia

Tarsitano

et al. 2013

Journal of Thrombosis and Haemostasis

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Intron 1 and intron 22 inversions (inv1 and inv22) represent the most prevalent mutations in the F8 gene (F8) (1-5% and 40-45%, respectively) causative of severe haemophilia A (HA) [1]. These alterations result from intrachromosomal recombination between intronic regions (int1h-1 and int22h-1, respectively) and their homologous extragenic copies in the telomeric position (int1h-2 and int22h-2/3, respectively) [1]. Inv1 causes an altered F8 structure with the translocation and inversion of the 5¢ region including exon 1 in the extragenic site, giving rise to two chimeric mRNAs: one containing the promoter and first exon of the F8 followed by some exons of the VBP1 gene; the other one formed by the promoter and coding sequences of the C6.1A gene joined to a part of the intron 1 and exons 2-26 of the F8 [2]. The clinical effect of this rearrangement is a severe phenotype with the absence of functional factor (F)VIII. According to literature data, the prevalence of inv1 ranges from 0% to 5% in severe HA patients from different countries [3,4]. In our cohort of 135 unrelated severe HA patients from Southern Italy, inv1 was found in four patients (2.9%) [5]. Here, we report the case of a severe HA patient, who showed an unusual pattern for inv1 associated with a complex gene rearrangement not described to date.The propositus is a Caucasian young male diagnosed with severe HA at the age of 1 year because of a positive family history. The causative F8 mutation in his affected uncle or the carrier status in his mother had not been previously searched for. The patient was treated with recombinant FVIII concentrates with no personal or family history of inhibitor development. We first analyzed the patient for both F8 inversions. This analysis excluded inv22 but showed a novel abnormal pattern for inv1, compared with those previously reported in literature, with two bands: one corresponding to the normal int1h-1 region (1908 bp) and the other corresponding to the band with the inversion of the int1h-1 sequence (1323 bp), as a heterozygous female, suggesting the presence of more than two copies of the int1h region (Fig. 1A). No bands of the int1h-2 region were detected, indicating a deletion within the homologous extragenic copy or a new rearrangement of sequences flanking the int1h-2 repeat not detectable by the PCR method used (Fig. 1A). We also investigated the presence of inv1 in his relatives: both mother and sister were carriers of the same aberrant pattern plus the 1191-bp fragment specific for the normal homologous extragenic int1h-2 sequence. The affected uncle was not available for molecular analysis. To confirm the direct diagnosis, linkage analysis was performed in this family, using intragenic (intron 18 BclI and intron 19 HindIII RFLP) and extragenic (DXS52 VNTR) polymorphisms, matching up with the same genetic profile. Furthermore, in the patient sequencing analysis of the F8, including all 26 exons, flanking intron/exon boundaries, promoter, 5¢ and 3¢ regions, did not reveal other mutations. In this family, a...

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confidence: 99%

Aberrant F8 gene intron 1 inversion with concomitant duplication and deletion in a severe hemophilia A patient from Southern Italy

Sanna

Ceglia

Tarsitano

et al. 2013

Journal of Thrombosis and Haemostasis

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“…Several gross complex rearrangements in F8, in addition to the well-known intron 22/1 inversions, have been reported. One of the first complex rearrangements in F8 because of slipped mispairing during replication and intragenic recombination was reported by Tavassoli et al 55 Furthermore, nonhomologous end-joining 56 and unequal homologous Alu-mediated recombination, 57,58 large deletions (20.7 kb) within the F8 gene involving long interspersed nuclear element-1 (LINE-1), 59 complex rearrangements consisting two deletion/insertion events at Xq28, 60 and a third inversion due to homologous recombination of inverted repeats within intron 1 61 have been described. The high frequency of micro/macro homologies and repetitive sequences predispose to pathological genomic rearrangements at Xq28.…”

Section: Large Genomic Rearrangementsmentioning

confidence: 94%

“…48,70 It could be speculated that in severe HA case where no mutation can be identified with the conventional methods, the cause for the disease might be related to breakpoints, large alterations, and rearrangements within the big intronic regions of F8. 61 Through these methods, novel intronic variations can be detected, which are localized in regions of F8 gene, which might explain the HA phenotype. Fig.…”

Section: State Of the Art F8 Gene Diagnosis And Beyondmentioning

confidence: 99%

Historical Review on Genetic Analysis in Hemophilia A

Oldenburg

Pezeshkpoor

Pavlova

2014

Semin Thromb Hemost

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Molecular genetic analysis is widely applied in inherited bleeding disorders. The outcome of genetic analysis allows genetic counselling in affected families and helps to find a link between the genotype and phenotype. Genetic analysis in hemophilia A (HA) has tremendously improved in the past decades. Many new techniques and modifications as well as analysis software have become available, which has enabled genetic analysis and interpretation of data to become faster and more accurate. The advances in mutation detection strategies facilitate the identification of the causal mutation in up to 97% of patients with HA. This review discusses the milestones in genetic analysis of HA and highlights the importance of identification of the causative mutations for genetic counseling and particularly for the interpretation of the clinical presentation of HA patients.

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“…In this case, the matching repeat sequence is situated 386 kb upstream of F8 in the IKBKG gene. The frequency of this rearrangement as a cause for hemophilia A is unknown [19].…”

Section: F8 Gene Defects Found In Hemophilia Amentioning

confidence: 99%