title: Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome.
abstract: Technological advances hold the promise of rapidly catalyzing the discovery of pathogenic variants for genetic disease. However, this possibility is tempered by limitations in interpreting the functional consequences of genetic variation at candidate loci. Here, we present a systematic approach, grounded on physiologically relevant assays, to evaluate the mutational content (125 alleles) of the 14 genes associated with Bardet-Biedl syndrome (BBS). A combination of in vivo assays with subsequent in vitro validation suggests that a significant fraction of BBS-associated mutations have a dominant-negative mode of action. Moreover, we find that a subset of common alleles, previously considered to be benign, are, in fact, detrimental to protein function and can interact with strong rare alleles to modulate disease presentation. These data represent a comprehensive evaluation of genetic load in a multilocus disease. Importantly, superimposition of these results to human genetics data suggests a previously underappreciated complexity in disease architecture that might be shared among diverse clinical phenotypes.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Norann A
authors.initials: NA
authors.lastname: Zaghloul
authors.forename: Yangjian
authors.initials: Y
authors.lastname: Liu
authors.forename: Jantje M
authors.initials: JM
authors.lastname: Gerdes
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gascue
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Oh
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Leitch
authors.forename: Yana
authors.initials: Y
authors.lastname: Bromberg
authors.forename: Jonathan
authors.initials: J
authors.lastname: Binkley
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
authors.forename: Arend
authors.initials: A
authors.lastname: Sidow
authors.forename: Jose L
authors.initials: JL
authors.lastname: Badano
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
mesh_terms: D000483:Alleles; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D023421:Models, Animal; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D015027:Zebrafish / Q000196:embryology / Q000235:genetics