title: Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome.
abstract: Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.
authors.affiliation: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Susanne
authors.initials: S
authors.lastname: Roosing
authors.affiliation: Department of Computer Science and Engineering, University of California, San Diego, San Diego, United States.
authors.forename: Matan
authors.initials: M
authors.lastname: Hofree
authors.affiliation: Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, United States.
authors.forename: Sehyun
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authors.lastname: Kim
authors.affiliation: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Scott
authors.affiliation: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Brett
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authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy.
authors.forename: Marta
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authors.lastname: Romani
authors.affiliation: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.affiliation: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Rasim O
authors.initials: RO
authors.lastname: Rosti
authors.affiliation: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Jana
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authors.lastname: Schroth
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy.
authors.forename: Tommaso
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authors.lastname: Mazza
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy.
authors.forename: Elide
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authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt.
authors.forename: Maha S
authors.initials: MS
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authors.affiliation: Departments of Neurology and Pediatrics, University of Utah School of Medicine, Salt Lake City, United States.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.affiliation: Department of Pediatric Genetics, University of New Mexico, Albuquerque, United States.
authors.forename: Joanne
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authors.lastname: Milisa-Drautz
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, United States.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Duke Institute for Brain Sciences, Duke University Medical Center, Durham, United States.
authors.forename: Mohamed A
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authors.lastname: Mikati
authors.affiliation: Department of Pediatric Neurology, Cukurova University Medical Faculty, Balcali, Turkey.
authors.forename: Faruk
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authors.lastname: İncecik
authors.affiliation: Department of Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan.
authors.forename: Matloob
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authors.lastname: Azam
authors.affiliation: Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.
authors.forename: Renato
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authors.lastname: Borgatti
authors.affiliation: Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Romaniello
authors.affiliation: Departments of Pediatrics, Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
authors.forename: Rose-Mary
authors.initials: RM
authors.lastname: Boustany
authors.affiliation: Division of Genetics/Dysmorphology, Department Pediatrics, University of New Mexico, Albuquerque, United States.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Clericuzio
authors.affiliation: Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Stefano
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authors.lastname: D'Arrigo
authors.affiliation: Women and Children's Division, Oslo University Hospital, Oslo, Norway.
authors.forename: Petter
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authors.affiliation: Department of Pediatric Neurology, University Children's Hospital, Zurich, Switzerland.
authors.forename: Eugen
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authors.affiliation: Department of Pediatrics, Genetic Counselling Service, Regional Hospital of Bolzano, Bolzano, Italy.
authors.forename: Franco
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authors.lastname: Stanzial
authors.affiliation: Child Neuropsychiatry Unit, Department of Neurosciences and Rehabilitation, Istituto G. Gaslini, Genoa, Italy.
authors.forename: Marisol
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authors.lastname: Mirabelli-Badenier
authors.affiliation: Unit of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Research Hospital, IRCCS, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Division of Nephrology and Dialysis, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Emma
authors.affiliation: University Children's Hospital, Berne, Switzerland.
authors.forename: Maja
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authors.lastname: Steinlin
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States.
authors.forename: Friedhelm
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authors.affiliation: Section of Ophthalmology and Neurosciences, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, United Kingdom.
authors.forename: Colin A
authors.initials: CA
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authors.affiliation: Neuropediatric group, Department of Paediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria.
authors.forename: Michael
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authors.lastname: Freilinger
authors.affiliation: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Keith K
authors.initials: KK
authors.lastname: Vaux
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: High Content Screening Systems, Sanford-Burnham Institute, La Jolla, United States.
authors.forename: Pedro
authors.initials: P
authors.lastname: Aza-Blanc
authors.affiliation: High Content Screening Systems, Sanford-Burnham Institute, La Jolla, United States.
authors.forename: Susanne
authors.initials: S
authors.lastname: Heynen-Genel
authors.affiliation: Department of Computer Science and Engineering, University of California, San Diego, San Diego, United States.
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
authors.affiliation: Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, United States.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dynlacht
authors.affiliation: Samsung Genome Institute, Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Mendel Institute, San Giovanni Rotondo, Italy.
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.affiliation: Korea Advanced Institute of Science and Technology, School of Medical Science and Engineering, Daejeon, Republic of Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Laboratory for Pediatric Brain Disease, New York Genome Center, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
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mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities*; D005124:Eye Abnormalities / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics; D050505:Mutant Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012160:Retina / Q000002:abnormalities*
chemical_list: D018797:Cell Cycle Proteins; C587687:KIAA0586 protein, human; D050505:Mutant Proteins; D034741:RNA, Small Interfering
keywords: Joubert syndrome; KIAA0586; Talpid3; ciliopathy; developmental biology; high-content screen; human; human biology; medicine; siRNA; stem cells