Alu enriched genomic structure facilitates chromosome 17p13.3 region susceptibility to diverse and complex pathogenic copy number variations. S. Gu1, B. Yuan1, I. M. Campbell1, A. Patel1, C. Bacino1, P. Stankiewicz1, S. W. Cheung1, W. Bi1, J. R. Lupski1,2 1) Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; 2) Texas Children's Hospital, Houston, TX.

   Copy number variants (CNVs) in human chromosome 17p13.3, a gene-rich region, are associated with various syndromes. Deletions of PAFAH1B1 (encoding LIS1) cause classical lissencephaly, while deletions of contiguous genes including both YWHAE and PAFAH1B1 cause Miller-Dieker syndrome with more severe lissencephaly and distinctive dysmorphic facial features. Duplications in 17p13.3 are also associated with diverse phenotypes. CNVs identified within 17p13.3 region are nonrecurrent, and mechanisms underlying these CNVs warrant further investigation. We identified 40 unrelated patients with copy number changes involving known disease genes or disease candidate genes within 17p13.3 using clinical chromosome microarrays. We performed customized high-density array comparative genomic hybridization (HD-aCGH) specifically interrogating the 17p13.3 region on all the patients with CNVs in this region, including thirteen patients with duplication, three with triplication, fourteen with deletion and ten with complex rearrangements. Breakpoint junctions were mapped at nucleotide resolution by PCR and DNA sequencing. In a total number of 28 breakpoint junctions determined, 17 (60.7%) had Alu repeats on both sides of the breakpoint junctions, while 4 breakpoint junctions (14.3%) had Alu repeats on one side of the breakpoint; thus, the majority of the CNVs appear to be Alu-facilitated events. The human 17p13.3 region has almost no segmental duplications, but this region is highly enriched for Alu repeats, with a fraction of around 30% comparing to the ~10% in the whole genome and ~18% on chromosome 17. Our studies suggest that Alu repeats may play an important role in the formation of nonrecurrent copy number changes and structural aberrations in 17p13.3.

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