Mutations causing hemophilia B in Algeria: Identification of two novel mutations of the factor 9 gene

Abla, Zidani; Yahia, Mouloud; Hejer, El Mahmoudi; Gouider, Emna; Abdi, Meriem; Ouarhlent, Yamina; Naouel, Salhi

doi:10.13057/biodiv/d190109

Cited by 5 publications

(10 citation statements)

References 32 publications

(35 reference statements)

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“…Nearly one third of hemophilia cases occur without any previous family history, but mainly due to new genetic variations [8]. In 1.3% to 7.8% of hemophilia cases, more than one mutation in the F9 gene have been reported [14], and, in accordance with other reports, most of the mutations were single nucleotide variants [15]. Missense mutations were the most common single nucleotide variants in HB, accounting for more than 58.4%, whereas 15.4% were frameshift mutations resulting from deletions, insertions, or duplications.…”

Section: Discussionsupporting

confidence: 83%

Mutation analysis and characterisation of F9 gene in haemophilia- B population of India

Kulkarni

Hegde²,

Hegde³

et al. 2021

Blood Res

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Background: Hemophilia B (HB) is an X-linked bleeding disorder resulting from coagulation factor IX (FIX) defects. Over 3,000 pathogenic, HB-associated mutations in the F9 gene have been identified. We aimed to investigate the role of F9 variants in 150 HB patients using sequencing technology.Methods: F9 gene sequences were amplified from peripheral blood-derived DNA and sequenced on an Applied Biosystems (ABI) 3500 Sanger sequencing platform. Functional and structural predictions of mutant FIX were analyzed.Results: Among 150 HB patients, 102 (68%), 30 (20%), and 18 (12%) suffered from severe, moderate, and mild HB, respectively. Genetic analysis identified 16 mutations, including 3 novel mutations. Nine mutations (7 missense and 2 stop-gain) were found to be pathogenic. Only 3 mutations (c.127C>T, c.470G>A, and c.1070G>A) were associated with different severities. While 2 mutations were associated with mild HB cases (c.304C>T and c.580A>G), 2 (c.195G>A and c.1385A>G) and 3 mutations (c.223C>T, c.1187G>A, and c.1232G>A) resulted in moderate and severe disease, respectively.Additionally, 1 mutation each was associated with mild-moderate (c.*1110A>G) and mild-severe HB disease (c.197A>T), 4 mutations were associated with moderate-severe HB cases (c.314A>G, c.198A>T, c.676C>T, and c.1094C>A). FIX concentrations were lower in the mutated group (5.5±2.5% vs. 8.0±2.5%). Novel p.E66D and p.S365 mutations were predicted to be pathogenic based on changes in FIX structure and function. Conclusion:Novel single nucleotide polymorphisms (SNPs) largely contributed to the pathogenesis of HB. Our study strongly suggests that population-based genetic screening will be particularly helpful to identify risk prediction and carrier detection tools for Indian HB patients.

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Section: Discussionsupporting

confidence: 83%

Mutation analysis and characterisation of F9 gene in haemophilia- B population of India

Kulkarni

Hegde²,

Hegde³

et al. 2021

Blood Res

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“…Interestingly, there are seventy patients' data available in the Factor IX Variant database reporting the detected nonsense mutation (NM_000133.3:c.880C>T, NP_ 000124.1:p.Arg294*) in exon 8, leading mostly to moderate and severe forms of the disease in patients from different ethnic backgrounds. In the current study, the severe form of the disease was observed in three studied patients (patients 4, 5, and 6) and their affected families members where factor IX activity was <1% [5,18,[23][24][25][26].…”

Section: Discussionmentioning

confidence: 99%

“…The two nonsense mutations (p.Arg294*, p.Arg384*) were detected in eight patients descending from four unrelated HB families (families 4, 5, 6, 7) who presented with the severe phenotype, were previously described in patients bearing moderate and severe forms of the disease [26] who stated that the nonsense mutations are expected to produce truncated unstable proteins as a result of premature translation or the involvement of the Nonsense-Mediated mRNA Decay (NMD) system regardless of their location. In addition, these two mutations (p.Arg294*, p.Arg384*) present in the serine protease domain; the greater part of which (codons 280-451) is coded by the largest exon in the F9 gene (exon 8), where CpG dinucleotides are considered to be mutation hot spots that are the highly susceptible site for mutation within the F9 gene [24][25][26][27][28][29].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, these two mutations (p.Arg294*, p.Arg384*) present in the serine protease domain; the greater part of which (codons 280–451) is coded by the largest exon in the F9 gene (exon 8), where CpG dinucleotides are considered to be mutation hot spots that are the highly susceptible site for mutation within the F9 gene [ 24 – 29 ].…”

Section: Discussionmentioning

confidence: 99%

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Defining the molecular pathology and consequent phenotypes in Egyptian HB patients

El‐Kamah

Mosaad²,

Taher

et al. 2021

Journal of Genetic Engineering and Biotechnology

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Background Hemophilia B (HB) (also known as Christmas disease) is a rare X-linked recessive disorder characterized by spontaneous or prolonged hemorrhages caused by mutations in Factor 9 (F9) gene leading to deficient or defective coagulation F9. Our study aimed at identifying the causative mutations within a sample of HB Egyptian patients. The present study comprised clinical data of eleven HB patients descending from six unrelated families and a seventh family including a carrier mother with a history of deceased HB sibling. Sequencing of F9 gene was performed. Results The study revealed four mutations; two missense NM_000133.3:c.676C>G, (P.Arg226Gly) and NM_000133.3:c.1305T>G, (p.Cys435Trp), and two nonsense mutations NM_000133.3:c.880C>T, (p.Arg294*) and NM_000133.3:c.1150C>T, (p.Arg384*), identified mutations spanned exons 6 and 8 of which a total of three mutations are located in hotspot exon 8 of F9 gene. Conclusions Reviewing the literature, this is the first molecular analysis of F9 gene in HB Egyptian patients. Consistent genotype/phenotypic severity correlation could be concluded, helping proper genetic counseling and prenatal decision taking.

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“…In a study by Abla et al, 24 demonstrate the importance of genetic testing to determine disease severity and predict complications. 24 Another study by Abla et al 30 aimed to identify F9 mutations in 39 patients from 13 unrelated families. PCR and direct sequencing identified nine point mutations, of which five were in exon 8 of the F9 gene.…”

Section: Genetic Testingmentioning

confidence: 99%

Haemophilia B in Algeria: Realities and therapeutic perspectives

Nekkal¹,

Mesli²,

Grifi

et al. 2023

Haemophilia

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IntroductionHaemophilia B is a debilitating hereditary coagulation disorder characterized by prolonged or spontaneous episodes of bleeding caused by a deficiency of endogenous factor IX. In Algeria, even though many studies are being carried out to evaluate the prevalence and management of haemophilia B, there is a paucity of locally published literature that can be used to understand the most recent information on the disease's epidemiology, diagnostic techniques and treatment options.AimsThe aim of this manuscript is to raise awareness among patients and family clinicians about current practices, recent developments and unmet needs related to haemophilia B in Algeria.MethodsA comprehensive literature search was conducted through online scientific databases to review publications regarding haemophilia B in Algeria. Exclusions of the review include case studies, interregional comparisons, abstract‐only papers and studies outside the range of 2012–2022.ResultsThe findings discussed relate to the epidemiology of haemophilia B in Algeria, the clinical diagnostic process, disease symptoms, the benefits of molecular and genetic testing, advancements in prophylactic care, as well as unmet needs hindering the progression of optimal haemophilia B management.ConclusionThese findings are crucial to encourage the maintenance of national registries with updated epidemiological data, facilitate early and timely detection of disease symptoms, improve the provision of diagnostic facilities and enhance the overall treatment landscape for better patient outcomes.

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Mutations causing hemophilia B in Algeria: Identification of two novel mutations of the factor 9 gene

Cited by 5 publications

References 32 publications

Mutation analysis and characterisation of F9 gene in haemophilia- B population of India

Mutation analysis and characterisation of F9 gene in haemophilia- B population of India

Defining the molecular pathology and consequent phenotypes in Egyptian HB patients

Haemophilia B in Algeria: Realities and therapeutic perspectives

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