Recurrent <i>F8</i> and <i>F9</i> gene variants result from a founder effect in two large French haemophilia cohorts

Lassalle, Fanny; Marmontel, Oriane; Zawadzki, C.; Frétigny, Mathilde; Bouvagnet, Patrice; Vinciguerra, Christine

doi:10.1111/hae.13480

Cited by 3 publications

(11 citation statements)

References 31 publications

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“…Detailed polymerase chain reaction (PCR) conditions for each marker have been previously described. 6…”

Section: Haplotype Analysismentioning

confidence: 99%

“…Several studies have reported a founder effect for other F8 variations found at a relatively high frequency in HA patients. [3][4][5][6][12][13][14][15] In these studies, the variations associated with a founder effect were found among a small number of selected patients and/or in a geographically isolated population. In contrast, herein, the DEL13T was found in a large number of apparently unrelated HA families from several areas of France.…”

Section: Essentialsmentioning

confidence: 99%

“…We used the ESTIAGE program 9 to estimate the age (expressed in number of generations) of the most recent common ancestor carrying the DEL13T, as previously described. 6…”

Section: Linkage Analysis and Estimation Of The Age Of The F8 C2113+4...mentioning

confidence: 99%

“…1,2 Founder effects have also been described for several F8 variations in isolated populations. [3][4][5][6] The main method to distinguish between founder effect and recurrent mechanism is to compare the haplotypes of closely linked markers, assuming that variants resulting from a founder effect share long identical haplotypes.…”

Section: Introductionmentioning

confidence: 99%

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The highly prevalent deletions in F8 intron 13 found in French mild hemophilia A patients result from both founder effect and recurrent de novo events

Jourdy

Frétigny

Lassalle

et al. 2020

Journal of Thrombosis and Haemostasis

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Background:Recently, our group has reported a 13-bp deletion in a poly(T)-track in the F8 intron 13 as the causative variant in approximately 6% of all cases of mild haemophilia A (HA) in France. The systematic screening of mild HA patients for this deletion identified individuals carrying deletions from 9 to 14-bp in the same region. Aims:To demonstrate that these highly prevalent deletions could result from a recurrent molecular mechanism and to determine the clinical significance of deletions other than 13-bp in size.Methods: Haplotype analysis using five polymorphic markers was performed in 71 unrelated French mild hemophilia A patients. Minigene analysis was performed to study the splicing impact of deletions from 1 to 14-bp. Results:A peculiar haplotype (H1) was identified in 22.5% of patients carrying the 13-bp deletion. Haplotypes differing from H1 only for the two most distal markers were found in more than the half of patients. These results confirmed the founder effect origin for the 13-bp deletion. However, the 9 patients carrying other sizes of deletion had a different haplotype suggesting that these deletions arose independently. Supporting the recurrent mechanism hypothesis, similar deletions were also found in 3/19 genetically unresolved mild Canadian patients. In vitro splicing analysis confirmed that deletions larger than 9-bp had a deleterious impact on splicing of F8 transcript. Conclusion:We demonstrated that the poly(T)-track in F8 intron 13 is a deletion hotspot. We recommend that deletions in this region should be specifically investigated in all genetically unresolved mild HA patients. K E Y W O R D SAlu element, founder effect, haemophilia A, haplotype, recurrent mechanism How to cite this article: Jourdy Y, Frétigny M, Lassalle F, Lillicrap D, Négrier C, Vinciguerra C. The highly prevalent deletions in F8 intron 13 found in French mild hemophilia A patients result from both founder effect and recurrent de novo events.

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“…Detailed polymerase chain reaction (PCR) conditions for each marker have been previously described. 6…”

Section: Haplotype Analysismentioning

confidence: 99%

Section: Essentialsmentioning

confidence: 99%

“…We used the ESTIAGE program 9 to estimate the age (expressed in number of generations) of the most recent common ancestor carrying the DEL13T, as previously described. 6…”

Section: Linkage Analysis and Estimation Of The Age Of The F8 C2113+4...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The highly prevalent deletions in F8 intron 13 found in French mild hemophilia A patients result from both founder effect and recurrent de novo events

Jourdy

Frétigny

Lassalle

et al. 2020

Journal of Thrombosis and Haemostasis

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“…The remaining two markers were extragenic; DF2 was located at the telomeric side of F8 , and DXS8061 was at the centromeric side. Detailed PCR conditions for each marker have been previously described 8,16 . The characteristics of each STR used in this study are listed in Table .…”

Section: Methodsmentioning

confidence: 99%

Identification of new F8 deep intronic variations in patients with haemophilia A

et al. 2020

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Haemophilia A (HA; OMIM 306700) is the most common X-linked recessive bleeding disorder, the incidence of which is 1 in 5,000 male births. HA is caused by quantitative or qualitative coagulation factor VIII (FVIII) deficiency. Based on residual FVIII activity (FVIII:C) levels in plasma, the HA phenotype is classified as either mild (5-40 IU.dL-1), moderate (1-<5 IU.dL −1) or severe (<1 IU. dL-1). 1 FVIII is encoded by the F8 gene (OMIM 300 841), located at Xq28 and spanning 186 kb. F8 is composed of 26 exons coding for

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A founder effect in hemophilia A patients from Russian Ural region with a new p.(His634Arg) variant in F8 gene

Salomashkina

Pshenichnikova

Perina

et al. 2021

Blood Coagulation &Amp; Fibrinolysis

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Hemophilia A is a clotting disease caused by defects in the F8 gene. A lot of them are described and most are unique or have polyphyletic origin. We here study the origin of a pathogenic variant found in a few patients. We sequenced F8 gene for seven hemophilia A patients from the Ural region, Sverdlovskaya oblast, Russia. We constructed haplotypes for them and for 21 hemophilia A patients with other defects from the same area as a control group using four previously described X-chromosome loci associated with F8 gene. We identified a new missense variant p.(His634Arg) in seven apparently unrelated patients with mild hemophilia A from Sverdlovskaya oblast. The haplotype analysis showed that all patients share the same haplotype, absent in the other patients, suggesting a founder effect. The most recent common ancestor for the p.(His634Arg) patients is estimated to exist around the end of XVII century; however, the 95% confidence interval spans from XII to early XX century. The Ural region did not suffer from the recent bottlenecks or isolation. Therefore, the founder effect could be a natural consequence of population structuring in a relatively stable population. We identified a founder effect mutation in hemophilia A, which is a quite rare event for this disease.

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Recurrent F8 and F9 gene variants result from a founder effect in two large French haemophilia cohorts

Cited by 3 publications

References 31 publications

The highly prevalent deletions in F8 intron 13 found in French mild hemophilia A patients result from both founder effect and recurrent de novo events

The highly prevalent deletions in F8 intron 13 found in French mild hemophilia A patients result from both founder effect and recurrent de novo events

Identification of new F8 deep intronic variations in patients with haemophilia A

A founder effect in hemophilia A patients from Russian Ural region with a new p.(His634Arg) variant in F8 gene

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