The Highly Prevalent Deletions in F8 Intron 13 Found in French Mild Haemophilia a Patients Result of Both Founder Effect and Recurrent De Novo Events
Bibliographic record
Abstract
Abstract Background: Genetic variations that are found at a relatively high frequency can be the consequence of a founder effect or repeated de novo events. Recently, our group has identified an intronic deletion, c.2113+461_2113+473del [DEL13T], in the F8 intron 13, in two mild haemophilia A patients. This deletion removed a part of the poly(T)-tail from the right arm of antisens AluY element and led to AluY exonisation. Then, deletions in the poly(T)-tail of AluY in F8 intron 13, from 10 to 14 pb in size, were found in approximately 6% of all cases of mild haemophilia in France. Aim: In this study, we determined whether these highly prevalent deletions are the result of recurrent molecular mechanism or of a founder effect. Methods: Haplotype reconstruction was performed after analysis of F8 extragenic and intragenic polymorphic markers in 71 unrelated French mild haemophilia A patients carrying a deletion in the poly(T)-tail of AluY in F8 intron 13 (c.2113+460_2113+473del [DEL14T] n=1; DEL13T, n=62; c.2113+462_2113+473del [DEL12T], n=2; c.2113+463_2113+473del [DEL11T], n=5 and c.2113+464_2113+473del, n=1 [DEL10T]) and in 50 non-haemophilia A subjects. The ESTIAGE tool was used to estimate the age of the DEL13T. Nineteen genetically unresolved mild Haemophilia A patients from Queen's University, Canada, were also included in the study. All patients and controls gave informed consent for genetic studies. Results: Two intragenic (STR13 and STR22) and 3 extragenic (DXS8061, ST14 and DF2) microsatellites were investigated in the DNA of the 71 mild haemophilia A patients. This set of polymorphisms markers covered a genomic region of 2,779,113 nucleotides (4.17 cM). Among the 62 patients carrying the DEL13T, 60 patients had the same allele for the marker directly flanking the deletion on the centromeric side (STR13, genetic distance 0.0062 cM). Two of them differed from the others at the next centromeric maker STR22 (genetic distance 0.2047 cM) and 20 patients differed from the others at ST14 (genetic distance 3.4237 cM). On the telomeric side, only 8 patients differed from the others at DF2 (genetic distance 0.0292 cM). None of control individuals shared such haplotypes with these 60 patients. These results provided evidence that the founder effect hypothesis was very plausible for the variant DEL13T. The ESTIAGE tool estimated that the DEL13T occurred about 61 generations ago (95% CI : 51-74 generations). Assuming that a generation spanned 25 years, the French common ancestor carrying the c.2113+461_2113+473del was estimated to have lived between the 2th and the 8th century. However, two patients carrying the DEL13T and 9 patients carrying the other deletions (DEL10T, DEL11T, DEL12T and DEL14T) had a different haplotype suggesting that these deletions arose independently. In order to support the hypothesis of a recurrent molecular mechanism, we have investigated the presence of these deletions in other geographies. F8 intron 13 deletions were found in 3/19 Canadian patients included in this study (DEL13T, n=2 and DEL10T, n=1). Haplotype analysis performed in these three patients suggested a de novo mechanism for two of them. Conclusion: This study supports both a founder effect for the c.2113+461_2113+473del in the French mild haemophilia A patients and a recurrent molecular mechanism leading to deletion in the poly(T)-tail of AluY in F8 intron 13. We recommended that these deletions be specifically investigated in all mild haemophilia A patients in whom no genetic abnormality has been detected by standard genetic analysis. Finally, these results suggest that large poly(T)-tail of inverted Alu elements may be a mutational hot spot and such deletions leading to alu-exonization, could occur in other genes. Disclosures Negrier: Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".