title: Genome-wide copy number variation analysis of a Branchio-oto-renal syndrome cohort identifies a recombination hotspot and implicates new candidate genes.
abstract: Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial arch anomalies, hearing loss and renal dysmorphology. Although haploinsufficiency of EYA1 and SIX1 are known to cause BOR, copy number variation analysis has only been performed on a limited number of BOR patients. In this study, we used high-resolution array-based comparative genomic hybridization on 32 BOR probands negative for coding-sequence and splice-site mutations in known BOR-causing genes to identify potential disease-causing genomic rearrangements. Of the >1,000 rare and novel copy number variants we identified, four were heterozygous deletions of EYA1 and several downstream genes that had nearly identical breakpoints associated with retroviral sequence blocks, suggesting that non-allelic homologous recombination seeded by this recombination hotspot is important in the pathogenesis of BOR. A different heterozygous deletion removing the last exon of EYA1 was identified in an additional proband. Thus, in total five probands (14 %) had deletions of all or part of EYA1. Using a novel disease-gene prioritization strategy that includes network analysis of genes associated with other deletions suggests that SHARPIN (Sipl1), FGF3 and the HOXA gene cluster may contribute to the pathogenesis of BOR.
authors.affiliation: Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Brophy
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Alasti
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Darbro
authors.forename: Jason
authors.initials: J
authors.lastname: Clarke
authors.forename: Carla
authors.initials: C
authors.lastname: Nishimura
authors.forename: Bryan
authors.initials: B
authors.lastname: Cobb
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Smith
authors.forename: J Robert
authors.initials: JR
authors.lastname: Manak
mesh_terms: D019280:Branchio-Oto-Renal Syndrome / Q000235:genetics*; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics / Q000502:physiology; D004252:DNA Mutational Analysis / Q000379:methods*; D051518:Fibroblast Growth Factor 3 / Q000235:genetics; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D014452:Ubiquitins / Q000235:genetics
chemical_list: C496444:FGF3 protein, human; D051518:Fibroblast Growth Factor 3; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C575183:SHARPIN protein, human; D014452:Ubiquitins; C088144:HoxA protein; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases