title: KIAA0586 is Mutated in Joubert Syndrome.
abstract: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. JS is part of a group of disorders called ciliopathies based on their overlapping phenotypes and common underlying pathophysiology linked to primary cilium dysfunction. Biallelic mutations in one of 28 genes, all encoding proteins localizing to the primary cilium or basal body, can cause JS. Despite this large number of genes, the genetic cause can currently be determined in about 62% of individuals with JS. To identify novel JS genes, we performed whole exome sequencing on 35 individuals with JS and found biallelic rare deleterious variants (RDVs) in KIAA0586, encoding a centrosomal protein required for ciliogenesis, in one individual. Targeted next-generation sequencing in a large JS cohort identified biallelic RDVs in eight additional families for an estimated prevalence of 2.5% (9/366 JS families). All affected individuals displayed JS phenotypes toward the mild end of the spectrum.
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.|Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Bachmann-Gagescu
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Phelps
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Dempsey
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Vivek A
authors.initials: VA
authors.lastname: Sharma
authors.affiliation: Department of Radiology, Seattle Children's Hospital, University of Washington, Seattle, Washington.
authors.forename: Gisele E
authors.initials: GE
authors.lastname: Ishak
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.|Department of Genetics, Stanford University, Stanford, Washington.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Boyle
authors.affiliation: Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, NSW, Australia.
authors.forename: Meredith
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Department of Neurosciences and Behavior Neurosciences, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors.forename: Charles
authors.initials: C
authors.lastname: Marques Lourenço
authors.affiliation: Gulhane Military Medical School, Division of Child Neurology, Ankara, Turkey.
authors.forename: Mutluay
authors.initials: M
authors.lastname: Arslan
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D001921:Brain / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics; D023061:Gene Order; D056726:Genetic Association Studies; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000175:diagnosis / Q000235:genetics; D008279:Magnetic Resonance Imaging; D009154:Mutation; D010641:Phenotype; D012160:Retina / Q000002:abnormalities*; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; C587687:KIAA0586 protein, human
keywords: Joubert syndrome; KIAA0586; Talpid3; ciliopathy; sonic hedgehog