Alport syndrome-diffuse leiomyomatosis is a rare type of X-linked Alport syndrome resulting from contiguous deletions of 5' exons of COL4A5 and COL4A6. Studies have suggested that the occurrence of diffuse leiomyomatosis is associated with the characteristic localisation of the COL4A6 gene deletion break point. An electronic database was searched for all studies accessing AS-DL to analyze the clinical characteristics, gene deletion break points of patients with AS-DL, and the pathogenesis of AS-DL. It was found that the proportion of de novo mutations of AS-DL was significantly higher in female probands than male probands (78 vs. 44%). Female patients with AS-DL had a mild clinical presentation. The incidence of proteinuria and ocular abnormalities was much lower in female probands than in male probands, and there was generally no sensorineural hearing loss or chronic kidney disease (CKD), which progressed to Stage 3 in female probands. The contiguous deletion of the 5' exons of COL4A5 and COL4A6, with the break point within the intron 3 of COL4A6, was the critical genetic defect causing AS-DL. However, the pathogenesis of characteristic deletion of COL4A6 that contributes to diffuse leiomyomatosis is still unknown. In addition, characteristic contiguous deletion of COL4A5 and COL4A6 genes in AS-DL may be related to transposed elements (TEs).

Alport syndrome-diffuse leiomyomatosis (AS-DL, OMIM: 308940) is a rare variant of the X-linked Alport syndrome that shows overgrowth of visceral smooth muscles in the gastrointestinal, respiratory and female reproductive tracts in addition to renal symptoms. AS-DL results from deletions that encompass the 5' ends of the COL4A5 and COL4A6 genes, but deletion breakpoints between COL4A5 and COL4A6 have been determined in only four cases. Here, we characterize deletion breakpoints in five AS-DL patients and show a contiguous COL4A6/COL4A5 deletion in each case. We also demonstrate that eight out of nine deletion alleles involved sequences homologous between COL4A5 and COL4A6. Most breakpoints took place in recognizable transposed elements, including long and short interspersed repeats, DNA transposons and long-terminal repeat retrotransposons. Because deletions involved the bidirectional promoter region in each case, we suggest that the occurrence of leiomyomatosis in AS-DL requires inactivation of both genes. Altogether, our study highlights the importance of homologous recombination involving multiple transposed elements for the development of this continuous gene syndrome and other atypical loss-of-function phenotypes.