Duchenne muscular dystrophy caused by a complex rearrangement between intron 43 of the DMD gene and chromosome 4.

Deletions/duplications of exons in the DMD gene cause about 70% of all cases of Duchenne muscular dystrophy (DMD). Most remaining mutations are point mutations or small insertion-deletions located mainly in the coding but also in deep intronic regions of the DMD gene. We describe a novel complex rearrangement in a patient affected with DMD that was undetectable using standard molecular diagnostic methods. Analysis of the proband's mRNA from a muscle biopsy revealed the insertion of an 80 bp cryptic exon from chromosome 4 between exons 43 and 44 of the dystrophin gene. Array comparative genomic hybridization and breakpoint junction sequence analysis indicated this cryptic exon originated from a complex genomic 90 kb insertion of non-coding chromosome 4 into intron 43 of the dystrophin gene. This rearrangement was also detectable in the patient's mother. The genomic characterization of this novel complex mutation was essential for accurate carrier and genetic counseling of this family and emphasizes the need for comprehensive molecular diagnosis of patients with clinical signs of DMD and clear pathological changes.