Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

Susanne Roosing, Matan Hofree, Sehyun Kim, Eric Scott, Brett Copeland, Marta Romani, Jennifer L Silhavy, Rasim O Rosti, Jana Schroth, Tommaso Mazza, Elide Miccinilli, Maha S Zaki, Kathryn J Swoboda, Joanne Milisa-Drautz, William B Dobyns, Mohamed A Mikati, Faruk İncecik, Matloob Azam, Renato Borgatti, Romina Romaniello, Rose-Mary Boustany, Carol L Clericuzio, Stefano D'Arrigo, Petter Strømme, Eugen Boltshauser, Franco Stanzial, Marisol Mirabelli-Badenier, Isabella Moroni, Enrico Bertini, Francesco Emma, Maja Steinlin, Friedhelm Hildebrandt, Colin A Johnson, Michael Freilinger, Keith K Vaux, Stacey B Gabriel, Pedro Aza-Blanc, Susanne Heynen-Genel, Trey Ideker, Brian D Dynlacht, Ji Eun Lee, Enza Maria Valente, Joon Kim, Joseph G Gleeson

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 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.