Molecular basis of haemophilia A

Oldenburg, Johannes; Ananyeva, Natalya M.; Saenko, Evgueni L.

doi:10.1111/j.1365-2516.2004.01005.x

Cited by 90 publications

(95 citation statements)

References 47 publications

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“…[24][25][26] In the first 3000 MLOF patients reported here, the spectrum of types of F8 and F9 genetic variants we found was similar to that previously reported in hemophilia, including in a report of 829 US patients with hemophilia A or B. [1][2][3][4][5]12,[27][28][29][30] Surprisingly, despite a long history of genetic studies in hemophilia, we identified 273 previously unreported F8 and F9 DNA variants, significantly advancing our knowledge of the genetics of hemophilia. Unique novel variants continued to be identified as the first 3000 patients were enrolled, suggesting that more novel variants will be detected as the project continues.…”

Section: Discussionsupporting

confidence: 73%

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Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

et al. 2017

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• MLOF used an innovative approach to genotype 3000 hemophilia patients identifying likely causative variants in 98.4% of patients.• Hemophilia genotyping should include structural variation, F8 inversions (for hemophilia A), and consideration of gene-wide approaches.Hemophilia A and B are rare, X-linked bleeding disorders. My Life, Our Future (MLOF) is a collaborative project established to genotype and study hemophilia. Patients were enrolled at US hemophilia treatment centers (HTCs). Genotyping was performed centrally using nextgeneration sequencing (NGS) with an approach that detected common F8 gene inversions simultaneously with F8 and F9 gene sequencing followed by confirmation using standard genotyping methods. Sixty-nine HTCs enrolled the first 3000 patients in under 3 years.Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. Of the 924 unique variants found, 285 were novel.Predicted gene-disrupting variants were common in severe disease; missense variants predominated in mild-moderate disease. Novel DNA variants accounted for ;30% of variants found and were detected continuously throughout the project, indicating that additional variation likely remains undiscovered. The NGS approach detected .1 reportable variants in 36 patients (10 females), a finding with potential clinical implications. NGS also detected incidental variants unlikely to cause disease, including 11 variants previously reported in hemophilia. Although these genes are thought to be conserved, our findings support caution in interpretation of new variants. In summary, MLOF has contributed significantly toward variant annotation in the F8 and F9 genes. In the near future, investigators will be able to access MLOF data and repository samples for research to advance our understanding of hemophilia.

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Section: Discussionsupporting

confidence: 73%

“…[1][2][3][4][5][27][28][29][30] Variants predicted to be gene-disrupting changes were detected predominantly in males with severe disease, as expected. SVs were more common in hemophilia A because of F8 intron 22 and intron 1 inversions, which accounted for 43% of severe male cases.…”

Section: Discussionmentioning

confidence: 65%

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

et al. 2017

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“…28,32 About 29% of all small deletions or insertions were found within exon 14 at one of two stretches of adenines: codons 1191-1194 (8A) and 1439-1441 (9A). 33 Overall, hot spots account for more than one-third of all point mutations in unrelated patients with HA (253/585; 43%). Exon 14 represents about one half of the coding region and encodes for the FVIII B domain, a region lacking procoagulant activity that is spliced out from the mature protein.…”

Section: Discussionmentioning

confidence: 99%

The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype

et al. 2008

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“…[1][2][3][4] Point mutations, deletions, and insertions were detected in all 26 exons of the F8 gene in HA patients, causing phenotypes of variable severity characterized by complete or partial deficiency of circulating FVIII. Large deletions in the F8 gene involving one or more exons account for about 5% of all severe HA cases, 5,6 (HADB (aka HAMSTeRS) the Hemophilia A Database, http://hadb.org.uk/). The identification of a large duplication comprising one or more F8 gene exons was recently made possible following the introduction of multiplex ligation-dependent probe amplification (MLPA) technology, with an estimated occurrence of 1%.…”

Section: Introductionmentioning

confidence: 99%

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

et al. 2013

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The intron 22 inversion found in up to 50% of severe hemophilia A patients results from a recombination between three intron 22 homologous copies (int22h). This study evaluated the implication of these copies in the formation of extended duplications comprising exons 1-22 of the factor 8 (F8) gene and their association with hemophilia and mental retardation. Two hemophilic patients with moderate and severe phenotypes and a third nonhemophilic patient with developmental delay were studied. All exhibited a duplication of F8 gene exons 1-22 identified by multiplex ligation-dependent probe amplification along with abnormal patterns on Southern blotting and unexpected long-range PCR amplification. Breakpoint analysis using array comparative genomic hybridization was performed to delimit the extent of these rearrangements. These duplications were bounded on one side by the F8 intragenic int22h-1 repeat and on the other side by extragenic int22h-2 or int22h-3 copies. However, the simultaneous identification of a second duplication containing F8 gene exons 2-14 for the moderate patient and the classical intron 22 inversion for the severe patient are considered in this study as the genetic causal defects of hemophilia. This study shows that the well-known int22h copies are involved in extended duplications comprising F8 gene exons 1-22. These specific duplications are probably not responsible for hemophilia and intellectual disability, but should be carefully considered in genetic counseling, while continuing to investigate the causal mutation of hemophilia.

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Molecular basis of haemophilia A

Cited by 90 publications

References 47 publications

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative

The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

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