Novel type of genetic rearrangement in the iduronate-2-sulfatase (IDS) gene involving deletion, duplications, and inversions

We describe a novel type of complex genetic rearrangement in the iduronate- 2-sulfatase (IDS) gene of a severely affected MPSII patient. Southern blot analysis indicated an intragenic deletion of exons 5 and 6. The deletion sp ans 5,581 bp. Sequencing of the deletion junctions revealed a complex rearr angement involving duplications and inversions. A remaining 20 bp fragment (c) from the intron 6 sequence and two duplicated IDS gene fragments of 314 bp (a) from intron 6/ exon 7 boundary and 23 bp (b) from exon 7 were found between the deletion breakpoints. Fragments a and c were placed in an inve rted orientation. We suggest that the described rearrangement is a result o f a nonhomologous recombination event at sites with little homology. The pr oposed model explaining this recombinational event involves the formation o f"tetra-loop" single-stranded DNA structure during replication. The complex ity of the described rearrangement and the lack of large homologous sequenc es at the mutational breakpoints suggest that complex molecular intermediat es are formed during illegitimate recombination, Hum Mutat 14:471-476, 1999 , (C) 1999 Wiley-Liss, Inc.