PUBLICATION

Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome

Authors
Lindstrand, A., Frangakis, S., Carvalho, C.M., Richardson, E.B., McFadden, K.A., Willer, J.R., Pehlivan, D., Liu, P., Pediaditakis, I.L., Sabo, A., Lewis, R.A., Banin, E., Lupski, J.R., Davis, E.E., Katsanis, N.
ID
ZDB-PUB-160804-5
Date
2016
Source
American journal of human genetics   99: 318-336 (Journal)
Registered Authors
Davis, Erica, Katsanis, Nicholas, Willer, Jason
Keywords
ciliopathy, mechanism of rearrangements, oligogenic disease, zebrafish model
MeSH Terms
  • Adolescent
  • Adult
  • Alleles
  • Animals
  • Bardet-Biedl Syndrome/genetics*
  • Child
  • Child, Preschool
  • Chromosome Breakpoints
  • Cytoskeletal Proteins/genetics
  • Cytoskeletal Proteins/metabolism
  • DNA Copy Number Variations/genetics*
  • Exons/genetics
  • Female
  • Gastrulation/genetics
  • Genes, Recessive
  • Humans
  • Infant
  • Male
  • Mutation*
  • Pedigree
  • Young Adult
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
27486776 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping