@article {30,
	title = {Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome.},
	journal = {Am J Hum Genet},
	volume = {99},
	year = {2016},
	month = {2016 Aug 04},
	pages = {318-36},
	abstract = {<p>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.</p>},
	keywords = {Adolescent, Adult, Alleles, Animals, Bardet-Biedl Syndrome, Child, Child, Preschool, Chromosome Breakpoints, Cytoskeletal Proteins, DNA Copy Number Variations, Exons, Female, Gastrulation, Genes, Recessive, Humans, Infant, Male, Mutation, Pedigree, Young Adult, Zebrafish, Zebrafish Proteins},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2015.04.023},
	author = {Lindstrand, Anna and Frangakis, Stephan and Carvalho, Claudia M B and Richardson, Ellen B and McFadden, Kelsey A and Willer, Jason R and Pehlivan, Davut and Liu, Pengfei and Pediaditakis, Igor L and Sabo, Aniko and Lewis, Richard Alan and Banin, Eyal and Lupski, James R and Davis, Erica E and Katsanis, Nicholas}
}
@article {16,
	title = {Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.},
	journal = {Am J Hum Genet},
	volume = {99},
	year = {2016},
	month = {2016 Nov 03},
	pages = {1005-1014},
	abstract = {<p>Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.</p>},
	keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 12, Complement C1r, Complement C1s, Ehlers-Danlos Syndrome, Endoplasmic Reticulum, Exome, Female, Gene Deletion, Genetic Loci, Humans, Male, Mutation, Missense, Pedigree, Periodontitis, Protein Conformation, Young Adult},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2016.08.019},
	author = {Kapferer-Seebacher, Ines and Pepin, Melanie and Werner, Roland and Aitman, Timothy J and Nordgren, Ann and Stoiber, Heribert and Thielens, Nicole and Gaboriaud, Christine and Amberger, Albert and Schossig, Anna and Gruber, Robert and Giunta, Cecilia and Bamshad, Michael and Bj{\"o}rck, Erik and Chen, Christina and Chitayat, David and Dorschner, Michael and Schmitt-Egenolf, Marcus and Hale, Christopher J and Hanna, David and Hennies, Hans Christian and Heiss-Kisielewsky, Irene and Lindstrand, Anna and Lundberg, Pernilla and Mitchell, Anna L and Nickerson, Deborah A and Reinstein, Eyal and Rohrbach, Marianne and Romani, Nikolaus and Schmuth, Matthias and Silver, Rachel and Taylan, Fulya and Vandersteen, Anthony and Vandrovcova, Jana and Weerakkody, Ruwan and Yang, Margaret and Pope, F Michael and Byers, Peter H and Zschocke, Johannes}
}
