Carrier and prenatal diagnostic strategy and newly identified mutations in Hungarian haemophilia A and B families

Bors, András; Andrikovics, Hajnalka; Illés, Z.; Jáger, Rita; Kardos, M; Marosi, Anikó; Nemes, L.; Tordai, Attila

doi:10.1097/mbc.0000000000000212

Cited by 8 publications

(4 citation statements)

References 30 publications

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“…Type I inversion 22 was found in 80-87.5% of cases, while type II was detected in 12.5-20% of the patients with inversion 22. Our results do not differ significantly from the reviewed studies, except for one report by Bors et al [22] from Hungary (p = 0.01). Inversion 1 was less studied, being reported only in nine studies with a frequency between 0% (in Poland, Bulgaria and Croatia) and 7.3% (in Macedonia).…”

Section: Discussioncontrasting

confidence: 82%

Large Intron Inversions in Romanian Patients with Hemophilia A—First Report

Brinza,

Grigore,

Dragomir

et al. 2023

Medicina

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Background and Objectives: Despite the vast heterogeneity in the genetic defects causing hemophilia A (HA), large intron inversions represent a major cause of disease, accounting for almost half of the cases of severe HA worldwide. We investigated the intron 22 and intron 1 inversion status in a cohort of Romanian unrelated patients with severe HA. Moreover, we evaluated the role of these inversions as relative risk factors in inhibitor occurrence. Materials and Methods: Inverse shifting—a polymerase chain reaction method was used to detect the presence of intron 22 and intron 1 inversions in 156 Romanian patients with HA. Results: Intron inversion 22 was found in 41.7% of the patients, while intron 1 inversion was detected in 3.2% of the patients. Overall, large intron inversions represented the molecular defect in 44.9% of the studied patients. Our findings are in accord with previously published reports from Eastern Europe countries and with other international studies. The risk of inhibitor development was higher in patients with inversion 1 compared to the patients with HA without any inversion detected. Conclusions: The current study demonstrates the major causative role of large intron inversions in severe HA in Romanian patients. Moreover, our study confirms the contribution of intron 1 inversion in inhibitor development.

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Section: Discussioncontrasting

confidence: 82%

Large Intron Inversions in Romanian Patients with Hemophilia A—First Report

Brinza,

Grigore,

Dragomir

et al. 2023

Medicina

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“…From the early 1990s, DNA sequencing was increasingly used to determine the familial mutation, and the majority of carrier status determination and PND is now undertaken with this analysis. However, a mix of linkage and sequence analysis can be used to provide a cost‐effective approach to carrier analysis and PND . Early PND at 11–14 weeks of gestation, amniocentesis at 16–18 weeks, and late gestation analysis at ≥ 32 weeks, also using amniocentesis, are all available, the last to inform delivery management for known carriers .…”

Section: Prenatal Diagnosismentioning

confidence: 99%

Hemophilia B: molecular pathogenesis and mutation analysis

Goodeve

2015

Journal of Thrombosis and Haemostasis

102

103

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SummaryHemophilia B is an X‐chromosome‐linked inherited bleeding disorder primarily affecting males, but those carrier females with reduced factor IX activity (FIX:C) levels may also experience some bleeding. Genetic analysis has been undertaken for hemophilia B since the mid‐1980s, through linkage analysis to track inheritance of an affected allele, and to enable determination of the familial mutation. Mutation analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in > 97% of patients with hemophilia B. The risk of the development of inhibitory antibodies, which are reported in ~ 2% of patients with hemophilia B, can be predicted, especially in patients with large deletions, and these individuals are also at risk of anaphylaxis, and nephrotic syndrome if they receive immune tolerance induction. Inhibitors also occur in patients with nonsense mutations, occasionally in patients with small insertions/deletions or splice mutations, and rarely in patients with missense mutations (p.Gln237Lys and p.Gln241His). Hemophilia B results from several different mechanisms, and those associated with hemophilia B Leyden, ribosome readthrough of nonsense mutations and apparently ‘silent’ changes that do not alter amino acid coding are explored. Large databases of genetic variants in healthy individuals and patients with a range of disorders, including hemophilia B, are yielding useful information on sequence variant frequency to help establish possible variant pathogenicity, and a growing range of algorithms are available to help predict pathogenicity for previously unreported variants.

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“…Direct sequence analysis provides definitive assessment of carrier status in HB 7. In the present study the procedure was conclusive in all the study participants.…”

Section: Discussionmentioning

confidence: 58%

Diagnosis and phenotypic assessment of Pakistani Haemophilia B carriers

et al. 2017

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Objectives:1: To assess the diagnostic utility of three polymorphisms (DdeI, XmnI and TaqI) and direct sequencing in haemophilia B (HB) carrier detection in Pakistani families. 2: To compare phenotypes of HB carriers with those of healthy females.Methods:The study was conducted from March 2014 till February 2016 at Khyber Medical University Peshawar and National Institute of Blood Diseases, Karachi. Individuals from HB families of Khyber Pakhtunkhwa (KP) and Federally Administered Tribal Areas (FATA) with known F9 mutation in the proband were enrolled into the study. FIX activity (FIX: C) levels were determined in all the participants. Bleeding scores (BS) and complete blood counts were performed in the female participants. Linkage analysis followed by targeted Sanger sequencing was carried out in all the study participants. Heterozygosity rate was determined for each polymorphism. Healthy females and the carrier groups were compared for bleeding phenotypes.Results:A total of 30 males and 48 females from 13 HB families were studied. The polymorphisms had a low heterozygosity rate. Direct sequencing determined the carrier status in all cases. The mean FIX: C was reduced whereas BS was raised in the carriers when compared with healthy females. A significant raise in white blood cells (WBCs) count was observed in the carriers.Conclusion:The three polymorphisms have a low heterozygosity rate in HB families from KP and FATA. Sanger sequencing is conclusive in determining carrier status in all the cases. FIX: C is low and BS is raised in the HB carriers in comparison to that of normal females. The mean WBCs count is significantly higher in the HB carriers than the normal females.

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Carrier and prenatal diagnostic strategy and newly identified mutations in Hungarian haemophilia A and B families

Cited by 8 publications

References 30 publications

Large Intron Inversions in Romanian Patients with Hemophilia A—First Report

Large Intron Inversions in Romanian Patients with Hemophilia A—First Report

Hemophilia B: molecular pathogenesis and mutation analysis

Diagnosis and phenotypic assessment of Pakistani Haemophilia B carriers

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