Tandem inversion duplication within F8 Intron 1 associated with mild haemophilia A. (11th May 2015)

• Record Type: Journal Article
• Authors: Lannoy, N.; Bandelier, C.; Grisart, B.; Reginster, M.; Ronge‐Collard, E.; Vikkula, M.; Hermans, C.
• Is Part Of: Haemophilia. Volume 21:Number 4(2015:Jul.)
• Page Start: 516
• Page End: 522
• Publication Date: 2015-05-11
• Subjects: Hemophilia -- Periodicals; 616.1572005
• DOI: 10.1111/hae.12675
• Languages: English
• ISSNs: 1351-8216

Abstract

<abstract abstract-type="main" id="hae12675-abs-0001"> <title>Summary</title> <p>In approximately 90% of mild haemophilia A (HA) patients, a missense mutation can be identified using complete gene sequencing. In this study, multiplex ligation‐dependent probe amplification analysis was performed as a second step in 10 French‐speaking Belgian with mild HA presenting no detectable causal mutation by complete sequencing of the factor VIII (FVIII) (<italic>F8</italic>) gene's 26 exons and its 1.2 kb of contiguous promoter sequence. This gene dosage technique enabled the detection of exon 1 duplications of <italic>F8</italic> in three apparently unrelated subjects. Using array‐comparative genomic hybridization, breakpoint analysis delimited the duplication extent to 210 kb in the <italic>F8</italic> intron 1 and <italic>VBP1</italic> gene intragenic position. We postulated that the rearrangement responsible for this duplication, never before reported, could be attributed to a symmetrical tandem inversion duplication, resulting in a large 233 kb rearrangement of <italic>F8</italic> intron 1. This rearranged intron should lead to the production of a small number of normal mRNA transcripts in relation to the mild HA phenotype. Our analysis of the entire <italic>F8</italic> mRNA from index case 1, particularly the segment containing exons 1–9, revealed normal amplification and sequencing. Reduced plasma FVIII antigen levels caused by cross‐reacting material is associated with a quantitative deficiency of plasma FVIII. Male patients were unresponsive to desmopressin (1‐deamino‐8‐D‐arginine vasopressin). All patients displayed identical <italic>F8</italic> haplotypes, despite not being related, which suggests a possible founder effect caused by a 210 kb duplication involving <italic>F8</italic> exon 1.</p> </abstract>