The alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles

摘要: Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions duplications in SPAST (mutations which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins molecular consequences remain obscure. We mapped breakpoint junctions 54 CNVs at nucleotide resolution. Diverse combinations exons are deleted or duplicated, highlighting importance particular for spastin function. Of CNVs, 38 (70%) appear be mediated by an Alu-based mechanism, suggesting that Alu-rich genomic architecture renders this locus susceptible various genome rearrangements. Analysis Alus further informs a model Alu-mediated CNV formation characterized small size potential involvement mechanisms other than homologous recombination. Twelve (22%) overlap part portion nearby, directly oriented gene, predicting novel chimeric genes these subjects’ genomes. cDNA from subject with final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating can transcriptional effects beyond gene itself. SLC30A6 has implicated Alzheimer disease, so data could explain report dementia cosegregating family SPAST. Our findings provide evidence Alu predisposes diverse alleles distinct transcriptional—and possibly phenotypic—consequences. Moreover, we mechanistic insights into change extendable loci.