title: Molecular analysis of a deletion hotspot in the NRXN1 region reveals the involvement of short inverted repeats in deletion CNVs.
abstract: NRXN1 microdeletions occur at a relatively high frequency and confer increased risk for neurodevelopmental and neurobehavioral abnormalities. The mechanism that makes NRXN1 a deletion hotspot is unknown. Here, we identified deletions of the NRXN1 region in affected cohorts, confirming a strong association with the autism spectrum and other neurodevelopmental disorders. Interestingly, deletions in both affected and control individuals were clustered in the 5' portion of NRXN1 and its immediate upstream region. To explore the mechanism of deletion, we mapped and analyzed the breakpoints of 32 deletions. At the deletion breakpoints, frequent microhomology (68.8%, 2-19 bp) suggested predominant mechanisms of DNA replication error and/or microhomology-mediated end-joining. Long terminal repeat (LTR) elements, unique non-B-DNA structures, and MEME-defined sequence motifs were significantly enriched, but Alu and LINE sequences were not. Importantly, small-size inverted repeats (minus self chains, minus sequence motifs, and partial complementary sequences) were significantly overrepresented in the vicinity of NRXN1 region deletion breakpoints, suggesting that, although they are not interrupted by the deletion process, such inverted repeats can predispose a region to genomic instability by mediating single-strand DNA looping via the annealing of partially reverse complementary strands and the promoting of DNA replication fork stalling and DNA replication error. Our observations highlight the potential importance of inverted repeats of variable sizes in generating a rearrangement hotspot in which individual breakpoints are not recurrent. Mechanisms that involve short inverted repeats in initiating deletion may also apply to other deletion hotspots in the human genome.
authors.affiliation: Capital Institute of Pediatrics, Beijing, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Chen
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Colby
authors.initials: C
authors.lastname: Chiang
authors.forename: Vamsee
authors.initials: V
authors.lastname: Pillalamarri
authors.forename: Ian
authors.initials: I
authors.lastname: Blumenthal
authors.forename: Michael
authors.initials: M
authors.lastname: Talkowski
authors.forename: Bai-Lin
authors.initials: BL
authors.lastname: Wu
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
mesh_terms: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004261:DNA Replication / Q000235:genetics; D059371:DNA, B-Form / Q000235:genetics; D004277:DNA, Single-Stranded / Q000235:genetics; D005091:Exons; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D055029:Inverted Repeat Sequences; D001523:Mental Disorders / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules; D017384:Sequence Deletion; D020079:Terminal Repeat Sequences
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D059371:DNA, B-Form; D004277:DNA, Single-Stranded; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules