Are int22h-mediated deletions a common cause of hemophilia?

Abstract

Hemophilia A (HA) (OMIM 306700) is an X-linked inherited bleeding disorder caused by deleterious mutations in the coagulation factor VIII gene (F8). Even though there is a broad diversity of HA-causative mutations, an uncommon type of rearrangement—a large DNA inversion involving F8 intron 22 (Inv22)—accounts for approximately one half of severely affected patients. Inv22 was formerly described by Lakich et al. [1] and Naylor et al. [2]. A collaborative international effort estimated that Inv22 is the cause of 43% (35%, 7%, and 1% for Inv22 type I, type II, and rare types, respectively) of severe HA cases worldwide with minor geographical or ethnical differences [3], in close agreement with our corresponding Argentinean series (42% of Inv22, and 34% and 7% for type I and type II, respectively) [4]. Naylor et al. [5] indicated that Inv22 originates by homologous recombination between well-defined duplicons (int22h) of 9.5 kb located one copy within F8 intron 22 (int22h-1, h1) and the other, inversely oriented, from a group of two extragenic copies (int22h-3, h3 for Inv22 type I and int22h-2, h2 for type II). It was formerly believed that h2 and h3 were equally oriented (i.e., head to tail). However, Ross et al. [6] determined that h2 and h3 are inversely oriented (i.e., head to head), both embedded in the arms of a large imperfect palindrome (Fig. 1). This finding prompted Bagnall et al. [7] to hypothesize recombination between these arms interchanging the location of the extragenic int22h copies and generating a non-deleterious inversion polymorphism in Xq28, i.e., h123 and h132. In this scenario, Inv22 type I may be generated from intrachromosomal recombination between h1 and h3 on the most frequent variant h123 whereas Inv22 type II may be generated between h1 and h2 on the least frequent h132 (Fig. 1). Moreover, on each of these normal structural variants of the X chromosome, recombination between h1 with either equally oriented copies (h2 or h3) may generate deletions (Del22) or duplications (Dup22) but not inversions [7]. More precisely, Del22 type I would be generated by recombination between h1 and h3 on variant h132 whereas Del22 type II by recombination between h1 and h2 on variant h123 [8] (Fig. 1).