| Author | Lindstrand, Anna | |
| Author | Frangakis, Stephan | |
| Author | Fonseca, Claudia Márcia Benedetto de Carvalho | |
| Author | Richardson, Ellen B. | |
| Author | McFadden, Kelsey A. | |
| Author | Willer, Jason R. | |
| Author | Pehlivan, Davut | |
| Author | Liu, Pengfei | |
| Author | Pediaditakis, Igor L. | |
| Author | Sabo, Aniko | |
| Author | Lewis, Richard Alan | |
| Author | Banin, Eyal | |
| Author | Lupski, James R. | |
| Author | Davis, Erica E. | |
| Author | Katsanis, Nicholas | |
| Access date | 2017-07-06T19:07:33Z | |
| Available date | 2017-07-06T19:07:33Z | |
| Document date | 2016 | |
| Citation | LINDSTRAND, Anna et al. Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome. Am J Hum Genet., v. 99, n. 2, p. 318-336, 2016 | pt_BR |
| ISSN | 0002-9297 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/19755 | |
| Language | eng | pt_BR |
| Publisher | Elsevier Inc | pt_BR |
| Rights | restricted access | pt_BR |
| Subject in Portuguese | Bardet-Biedl | pt_BR |
| Title | Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome. | pt_BR |
| Type | Article | |
| DOI | 10.1016/j.ajhg.2015.04.023 | |
| Abstract | Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture. | pt_BR |
| Affilliation | Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
| Affilliation | Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
| Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brazil | pt_BR |
| Affilliation | Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
| Affilliation | Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
| Affilliation | Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
| Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA | pt_BR |
| Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA | pt_BR |
| Affilliation | Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
| Affilliation | Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
| Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/ Baylor College of Medicine. Human Genome Sequencing Center. Houston, USA | pt_BR |
| Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Baylor College of Medicine. Department of Ophthalmology. Houston, USA | pt_BR |
| Affilliation | Hadassah-Hebrew University Medical Center. Department of Ophthalmology. Center for Retinal and Macular Degenerations. Jerusalem, Israel | pt_BR |
| Affilliation | Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA/Baylor College of Medicine. Human Genome Sequencing Center. Houston, USA/Baylor College of Medicine. Department of Pediatrics. Houston, TX, USA/Texas Children’s Hospital. Houston, TX, USA | pt_BR |
| Affilliation | Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
| Affilliation | Duke University School of Medicine. Center for Human Disease Modeling. Durham, NC, USA | pt_BR |
| Subject | ciliopathy | pt_BR |
| Subject | mechanism of rearrangements | pt_BR |
| Subject | oligogenic disease | pt_BR |
| Subject | zebrafish model | pt_BR |
| Embargo date | 2023-01-01 | |
