Analysis of factor VIII gene intron 1 inversion in Argentinian families with severe haemophilia A and a review of the literature

Abstract

Besides intron 22 factor VIII gene inversion (Inv22), intron 1 inversion (Inv1) has recently been reported as a further recurrent mutation that causes approximately 5% of severe haemophilia A (HA) cases. We analysed the presence of the Inv1 in a group of 64 severe HA-affected families from Argentina, and found only one positive case. This Inv1 patient has not developed a factor VIII inhibitor, and the screening for small mutations in the coding sequences of the factor VIII gene did not detect any additional defect in this case. The Inv1 genotyping was further applied to analyse the haemophilia carrier status of the proband's sister. In addition, we studied the accuracy of the current polymerase chain reaction-based method to investigate the Inv1, and confirmed the absence of amplimer length polymorphisms associated to the Inv1-specific polymerase chain reaction amplifications in 101 X-chromosome haplotypes from unrelated Argentinian healthy males. In order to discuss Inv1 mutation frequency in severe HA and the risk of inhibitor formation, a review of the literature was included. Our data highlight the importance of analysis of the Inv1 in Inv22-negative severe HA cases. This will benefit both genetic counselling and the study of the relationship between genotype and inhibitor development.

Genetic analysis of haemophilia A in Taiwan

“…There were 5.2% (6 of 115) patients with intron 1 inversion in our study and 3.3% (3 of 91) unrelated families had this mutation, which is slightly higher than the 0.7-2.7% reported in the literature (Table 1). Furthermore, 7.6% of 79 severe HA patients in our study were found to have this inversion, which is apparently higher than the 2-5% reported in the literature [3,7,31]. Aside from the high frequency of intron 22 and 1 inversions, HA is caused by a large variety of less frequent mutations scattered throughout the 26 exons of FVIII gene.…”

Frequency of intron 1 and 22 inversions of factor VIII gene in Mexican patients with severe hemophilia A

“…The frequency of inv1 recently estimated in the general population is <5% [14,19] as it was indeed originally described for a UK severe HA population [3]; however, detailed haplotype analyses would lead to a more reliable figure.…”

“…Even though different patterns of recombination have been described in addition to the distal and proximal most common mechanisms [4,11], there is a nonsignificant variance in the frequency of inv22 among populations. Consistently, this inversion causes 40-50% of severe HA cases in all studied populations [2][3][4]11,[13][14][15][16][17][18], a figure related to the characteristics of intragenic and extragenic homologue copies: the telomeric position of the latter copies (the distal being five times more frequent than the proximal inversion) [2] and the large size of the involved fragments (9.5 kb). Because the subjacent mechanism is similar for both rearrangements, the notable 10 times lower frequency for inv1 inversion is probably related to a populationspecific genetic background that promotes recombination and is rather common in certain populations [3] but not in others [11].…”

“…We used Pearson x 2 comparison or Fisher exact test depending on the values expected for frequencies in cross-tab for comparing inv22 and inv1 frequencies of Mexican patients with other severe HA populations including Argentina [13,14], Hungary [11], India [15], Italy [16], Spain [17,18], and UK [3]. A 2 Â 2 cross-tab was used for analyzing the association between inversion 22 and development of FVIII inhibitors.…”

Genetic testing in bleeding disorders

“…Using Southern blotting, molecular diagnosis of Inv22 has been available in Argentina since 1995. Shortly after the second recurrent inversion affecting F8, intron 1 (Inv1), was described, our series was reported along with a review of the literature estimating that Inv1 causes <3% of severe-HA in Argentina [1]. Inv22 originates from homologous recombination between a 9.5 kb sequence located within F8 intron 22 (int22h-1) and one of two oppositely oriented extragenic copies of int22h (int22h-2 and int22h-3) located by the Xq-telomere.…”