Overrepresentation of missense mutations in mild hemophilia A patients from Belgium: founder effect or independent occurrence?

Lannoy, Nathalie; Lambert, C. T.; Vikkula, Miikka; Hermans, Cédric

doi:10.1016/j.thromres.2015.03.017

Cited by 6 publications

(8 citation statements)

References 14 publications

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“…Considering that F9‐Pt20, F9‐Pt18, F9‐Pt32 and F9‐Pt4 could also have a de novo variant changed ESTIAGE estimation to 47 generations (95% CI: 36‐61, 5th‐12th century). The occurrence of de novo variants at this position was consistent with the fact that c.835G>A occurred within a CpG dinucleotide, a sequence prone to variants in F9 and F8 . A few other cases were described in different countries in Europe, India, United States and Argentina but the frequency of this pathogenic variant was much higher in the Auvergne‐Rhône‐Alpes region, with a prevalence of 40% among the mild HB patients.…”

Section: Discussionsupporting

confidence: 73%

“…4,5 The identification of the same pathogenic variant in several patients from the same geographic region has been previously described in several publications. Haemophilia A is associated with the variant c.6069G>A, p.Ser2030Asn in Belgium 6 and c.6046C>T, p.Arg2016Trp in Northern Italy. 7 Haemophilia B is associated with the Leyden variant c.-35G>A in Ireland.…”

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confidence: 99%

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

et al. 2018

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Introduction Haemophilia A (HA) and haemophilia B (HB) are X‐linked recessive diseases, caused by a large number of pathogenic variants in the F8 and F9 genes. With the exception of introns 22 and 1 inversions which are frequent in severe HA cases, about 2000 unique variants in F8 and 1000 in F9 have been described in databases and their recurrence remains limited. Aim and methods During routine analysis, we identified two recurrent missense variants, the F8 gene c.1244C>T, p.Ala415Val variant in 27 HA patients and the F9 gene c.835G>A, p.Ala279Thr variant in 34 HB patients, in two groups of haemophiliac patients from two different regions of France. We aimed to identify whether these variants result from a founder effect. We performed haplotype reconstruction after analysis of extragenic and intragenic polymorphic markers. The ESTIAGE programme was used to estimate the age of the variant. Results We identified a common ancestral haplotype HA1, in all the HA patients sharing the p.Ala415Val variant, and HB1 for 22 of 34 HB patients sharing the p.Ala279Thr variant. The estimated time of occurrence of the founder variant was between the 13th and 17th century (95% CI: 16 to 29 generations) for the F8 variant and between the 3rd and the 11th century for the F9 variant (95% CI: 44 to 72 generations). Conclusion This study supports a founder effect for these two variants in the two largest reported cohorts of haemophilia patients with an identical variant. These pathogenic variants are among the three most early reported variants in haemophilia.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

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

et al. 2018

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“…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.…”

Section: Resultsmentioning

confidence: 96%

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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“…In contrast, the number of successive female cell divisions from zygote to mature egg is only 24, approximately 30 . Moreover, many variants arise at sites that mutate at unusually high rates, such as CpG dinucleotide sites 31 . Methylation has been suggested to occur at a much higher rate in spermatocyte DNA than oocyte DNA, thereby increasing the point variant frequency of paternal, rather than maternal, origin 32 …”

Section: Mosaicism In Haemophilia and Implications For Patientsmentioning

confidence: 99%

Genetic mosaicism in haemophilia: A practical review to help evaluate the risk of transmitting the disease

Lannoy¹,

Hermans²

2020

Haemophilia

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Approximately 70% of patients with haemophilia exhibit a clear inheritance pattern, while for the remaining 30%, patients are the first to be diagnosed in their family and are considered sporadic cases. In such a setting, the determination of carrier status and the risk estimation of disease transmission to another child are major challenges for genetic counselling. Large studies have suggested that genetic testing reveals 70% of sporadic patients' mothers are carriers. In the remaining 30%, in some apparently non-carrier mothers, the pathogenic variant can be detected as low somatic and gonosomal mosaicism. The significance of mosaic pathogenic variants has thus far been underestimated, since conventional Sanger sequencing and other technology are not sufficiently sensitive. The study of various tissue samples and recent extrasensitive molecular methods have now made it easier to detect both single-nucleotide variants (SNVs) and copy-number variants (CNVs), at a mosaic level in parents, and to predict the probability of disease recurrence. This review seeks to examine various kinds of mosaicism in haemophilia, including the mechanisms by which they arise and the risk of passing these variants on to the next generation. In addition, we focus on the selection of cell tissues and methods to detect these mosaic variants in the haemophilia setting. Taking into account the high rate of mosaicism in mothers of sporadic cases, we propose a diagnostic flow chart that could facilitate better evaluation of the risk of transmitting haemophilia in genetic and prenatal counselling. K E Y W O R D S

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Overrepresentation of missense mutations in mild hemophilia A patients from Belgium: founder effect or independent occurrence?

Cited by 6 publications

References 14 publications

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

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

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

Genetic mosaicism in haemophilia: A practical review to help evaluate the risk of transmitting the disease

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