An aberrant pattern for intron 1 inversion of factor VIII gene

Pio, S. F.; Oliveira, Guilherme; Soares, Sheila; Rezende, Suely Meireles

doi:10.1111/j.1365-2516.2010.02482.x

Cited by 5 publications

(7 citation statements)

References 5 publications

(11 reference statements)

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“…To date, aberrant diagnostic patterns of Inv1 have been reported in several studies (7)(8)(9)(10). These unusual Inv1 rearrangements, often found with complex duplication/deletion rearrangements, might be caused by the possible presence of extra copies of the int1h region or segmental duplications of the F8 gene.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterisation of a novel aberrant pattern of intron 1 inversion with concomitant large insertion and deletion within the F8 gene

You¹,

Chi²,

Lu³

et al. 2014

Thromb Haemost

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Intron 1 inversion (Inv1) is a recurrent causative mutation of haemophilia A (HA) and is responsible for 1-5% of severe HA. Inv1 occurs as a result of intra-chromosomal homologous recombination between int1h-1 within intron 1 and int1h-2 located in approximately 125 kb telomeric to the F8 gene. In this report, we presented a previously undescribed aberrant type of Inv1 with complex genomic rearrangement in a pedigree with severe HA. The breakpoints of the rearrangement were identified by the genome walking technique; copy number variations (CNVs) of the F8 gene and X chromosome were detected by AccuCopy technique, Affymetrix CytoScan HD CNV assay and quantitative PCR (qPCR); the F8 transcripts related to the aberrant Inv1 were analysed by reverse transcription PCR (RT-PCR). We have characterised the exact breakpoints of the complex rearrangement, and determined the location and size of the insertion and deletion. The rearrangements can be summarised as an aberrant pattern of Inv1 with a deletion of 2.56 kb and a duplication of 227.3 kb inserted in the rejoining junction within the F8 gene. Our results suggested that this complex genomic rearrangement was generated by two distinct repair mechanisms of fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) and nonallelic homologous recombination (NAHR).

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Section: Introductionmentioning

confidence: 99%

Identification and characterisation of a novel aberrant pattern of intron 1 inversion with concomitant large insertion and deletion within the F8 gene

You¹,

Chi²,

Lu³

et al. 2014

Thromb Haemost

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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).…”

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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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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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Section: Genetic Analysismentioning

confidence: 99%

“…The presence of inversions of introns 1 and 22 have been reported as responsible for approximately 5 and 45% of severe hemophilia A phenotypes, respectively [27][28][29]. Analysis of introns 1 and 22 are performed in all patients with hemophilia A with FVIII:C less than 2%, with the inverse PCR technique, according to protocols already established [27,28]. Samples of nonsevere patients with hemophilia A and for the ones who are not carriers of introns 1 and 22 inversion and samples of all patients with hemophilia B are sequenced.…”

Section: Genetic Analysismentioning

confidence: 99%

Risk factors for antibody formation in children with hemophilia: methodological aspects and clinical characteristics of the HEMFIL cohort study

Jardim

Santana

Chaves

et al. 2021

Blood Coagulation &Amp; Fibrinolysis

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Up to 35% of patients with hemophilia A and 5% with hemophilia B develop neutralizing antibodies which can inhibit the therapeutic activity of factor replacement (inhibitors). Despite the clinical relevance of antifactor VIII and IX neutralizing antibodies, there is still a major gap on the knowledge of risk factors for their development. Furthermore, most of the studies on risk factors for inhibitor development come from Caucasian and Afro-American populations. The HEMFIL is a Brazilian prospective cohort study of previously untreated children with hemophilia, which primary aim is to identify new risk factors related to inhibitor development. This manuscript aims at describing the study design and its methodology. After the diagnosis, children are followed up to 75 exposure days or to inhibitor development. Standardized forms and blood samples are collected to describe clinical characteristics and to perform the measurement of immunological and genetic biomarkers at three time points; Inclusion time (T0), at inhibitor development or at 75 exposure days without inhibitors (T1) and after immune tolerance induction for patients in whom it is indicated and performed (T2). Currently, 120 children have been included, of whom, 95 have completed the follow-up. For severe/moderately severe hemophilia A, the cumulative incidence of inhibitors at 75 exposure days was 35% (95% confidence interval, 26–46%). The inclusion of additional patients and a longer follow-up will allow the analysis of risk factors for inhibitor development.

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An aberrant pattern for intron 1 inversion of factor VIII gene

Cited by 5 publications

References 5 publications

Identification and characterisation of a novel aberrant pattern of intron 1 inversion with concomitant large insertion and deletion within the F8 gene

Identification and characterisation of a novel aberrant pattern of intron 1 inversion with concomitant large insertion and deletion within the F8 gene

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

Risk factors for antibody formation in children with hemophilia: methodological aspects and clinical characteristics of the HEMFIL cohort study

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