Journal article
Genome-wide copy number variation analysis of a Branchio-Oto-Renal syndrome cohort identifies a recombination hotspot and implicates new candidate genes
Human genetics, Vol.132(12), pp.1339-1350
12/2013
DOI: 10.1007/s00439-013-1338-8
PMCID: PMC3830662
PMID: 23851940
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 (aCGH) 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 (CNVs) 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 5 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.
Details
- Title: Subtitle
- Genome-wide copy number variation analysis of a Branchio-Oto-Renal syndrome cohort identifies a recombination hotspot and implicates new candidate genes
- Creators
- Patrick D Brophy - Dept of Pediatrics, Univ of Iowa Carver College of Medicine, Iowa City, IA, 52242, USAFatemeh Alasti - Dept of Otolaryngology, Univ of Iowa Carver College of Medicine, Iowa City, IA, 52242, USABenjamin W Darbro - Dept of Pediatrics, Univ of Iowa Carver College of Medicine, Iowa City, IA, 52242, USAJason Clarke - Dept of Pediatrics, Univ of Iowa Carver College of Medicine, Iowa City, IA, 52242, USACarla Nishimura - Dept of Otolaryngology, Univ of Iowa Carver College of Medicine, Iowa City, IA, 52242, USABryan Cobb - Dept of Biology, Univ of Iowa, Iowa City, IA, 52242, USARichard J Smith - Dept of Otolaryngology, Univ of Iowa Carver College of Medicine, Iowa City, IA, 52242, USAJ. Robert Manak - Dept of Pediatrics, Univ of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.132(12), pp.1339-1350
- DOI
- 10.1007/s00439-013-1338-8
- PMID
- 23851940
- PMCID
- PMC3830662
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Grant note
- R01 DC003544 || DC / National Institute on Deafness and Other Communication Disorders : NIDCD
- Language
- English
- Date published
- 12/2013
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Biology; Craniofacial Anomalies Research Center; Otolaryngology; Internal Medicine
- Record Identifier
- 9984007157802771
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