{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:37:17Z","timestamp":1792643837588,"version":"4.5.0"},"reference-count":121,"publisher":"SAGE Publications","issue":"1-2","license":[{"start":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T00:00:00Z","timestamp":1562198400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Translational Science of Rare Diseases"],"published-print":{"date-parts":[[2019,7,4]]},"abstract":"<jats:p>Joubert syndrome (JS; MIM PS213300) is a rare, typically autosomal recessive disorder characterized by cerebellar vermis hypoplasia and a distinctive malformation of the cerebellum and brainstem identified as the \u201cmolar tooth sign\u201d on brain MRI. Other universal features include hypotonia with later ataxia and intellectual disability\/developmental delay, with additional features consisting of oculomotor apraxia and abnormal respiratory pattern. Notably, other, more variable features include renal cystic disease, typically nephronophthisis, retinal dystrophy, and congenital hepatic fibrosis; skeletal changes such as polydactyly and findings consistent with short-rib skeletal dysplasias are also seen in many subjects. These pleiotropic features are typical of a number of disorders of the primary cilium, and make the identification of causal genes challenging given the significant overlap between JS and other ciliopathy conditions such as nephronophthisis and Meckel, Bardet-Biedl, and COACH syndromes. This review will describe the features of JS, characterize the 35 known genes associated with the condition, and describe some of the genetic conundrums of JS, such as the heterogeneity of founder effects, lack of genotype-phenotype correlations, and role of genetic modifiers. Finally, aspects of JS and related ciliopathies that may pave the way for development of therapeutic interventions, including gene therapy, will be described.<\/jats:p>","DOI":"10.3233\/trd-190041","type":"journal-article","created":{"date-parts":[[2019,7,5]],"date-time":"2019-07-05T10:57:59Z","timestamp":1562324279000},"page":"25-49","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":63,"title":["The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity"],"prefix":"10.1177","volume":"4","author":[{"given":"Melissa A.","family":"Parisi","sequence":"first","affiliation":[{"name":"Chief, Intellectual & Developmental Disabilities Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,7,4]]},"reference":[{"key":"ref001","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.11.015"},{"key":"ref002","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.06.003"},{"key":"ref003","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.08.015"},{"key":"ref004","unstructured":"ArtsH. and KnoersN., Cranioectodermal Dysplasia, 2013 Sep 12 [Updated 2018 Apr 12]. In: M.P. Adam, H.H. Ardinger, R.A. Pagon, et al., editors. GeneReviews\n                      \u00ae\n                      [Internet]. Seattle (WA): University of Washington, Seattle;1993\u20132019."},{"key":"ref005","doi-asserted-by":"publisher","DOI":"10.1086\/510499"},{"key":"ref006","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2015-103087"},{"key":"ref007","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005575"},{"key":"ref008","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2011-100552"},{"key":"ref009","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22821"},{"key":"ref010","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22618"},{"key":"ref011","doi-asserted-by":"publisher","DOI":"10.1038\/ng.423"},{"key":"ref012","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2018.03.012"},{"key":"ref013","doi-asserted-by":"publisher","DOI":"10.1086\/519026"},{"key":"ref014","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-5-20"},{"key":"ref015","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20924"},{"key":"ref016","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2018.05.026"},{"key":"ref017","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.06.023"},{"key":"ref018","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.06.028"},{"key":"ref019","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2410"},{"key":"ref020","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.09.002"},{"key":"ref021","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43639"},{"key":"ref022","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.08.017"},{"key":"ref023","doi-asserted-by":"publisher","DOI":"10.1038\/ng2039"},{"key":"ref024","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38158"},{"key":"ref025","doi-asserted-by":"publisher","DOI":"10.1086\/425985"},{"key":"ref026","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2009.06.002"},{"key":"ref027","doi-asserted-by":"publisher","DOI":"10.1002\/pd.1145"},{"key":"ref028","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.067249"},{"key":"ref029","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2018.05.014"},{"key":"ref030","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.12.007"},{"key":"ref031","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2017.02.065"},{"key":"ref032","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2012.9"},{"key":"ref033","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.05660517"},{"key":"ref034","unstructured":"ForsytheE. and BealesP.L. (2015) Bardet-Biedl Syndrome, 2003 Jul 14 [Updated 2015 Apr 23]., In: M.Adam, H.H. Ardinger, R.A. Pagon, et al., editors. GeneReviews\n                      \u00ae\n                      [Internet]. Seattle (WA): University of Washington, Seattle; 1993\u20132019."},{"key":"ref035","doi-asserted-by":"publisher","DOI":"10.1038\/ng.891"},{"key":"ref036","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028134"},{"key":"ref037","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20437"},{"key":"ref038","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2017.0054"},{"key":"ref039","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.10.002"},{"key":"ref040","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30225"},{"key":"ref041","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2009.03.045"},{"key":"ref042","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.09.012"},{"key":"ref043","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2017.00244"},{"key":"ref044","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008050456"},{"key":"ref045","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1997.31"},{"key":"ref046","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2007020243"},{"key":"ref047","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.11.005"},{"key":"ref048","doi-asserted-by":"publisher","DOI":"10.1038\/ng.427"},{"key":"ref049","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.19.9.813"},{"key":"ref050","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063525"},{"key":"ref051","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9489"},{"key":"ref052","doi-asserted-by":"publisher","DOI":"10.1038\/ng.366"},{"key":"ref053","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.84"},{"key":"ref054","unstructured":"KumaranN., PennesiM.E., YangP., TrzupekK.M., SchlechterC., MooreA.T., WeleberR.G. and MichaelidesM. (2018) Leber Congenital Amaurosis \/ Early-Onset Severe Retinal Dystrophy Overview, 2018 Oct 4. In: M.P. Adam, H.H. Ardinger, R.A. Pagon, et al., editors. GeneReviews\n                      \u00ae\n                      [Internet]. Seattle (WA): University of Washington, Seattle; 1993\u20132019."},{"key":"ref055","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3273"},{"key":"ref056","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1078"},{"key":"ref057","doi-asserted-by":"publisher","DOI":"10.1126\/science.1213506"},{"key":"ref058","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33416"},{"key":"ref059","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.04.023"},{"key":"ref060","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-013-1385-1"},{"key":"ref061","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23054"},{"key":"ref062","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2015-103316"},{"key":"ref063","doi-asserted-by":"publisher","DOI":"10.1177\/088307389901400906"},{"key":"ref064","doi-asserted-by":"publisher","DOI":"10.1177\/088307389701200703"},{"key":"ref065","doi-asserted-by":"publisher","DOI":"10.1177\/088307389901400605"},{"key":"ref066","doi-asserted-by":"publisher","DOI":"10.1002\/path.4843"},{"key":"ref067","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30406"},{"key":"ref068","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21116"},{"key":"ref069","doi-asserted-by":"publisher","DOI":"10.1093\/ckj\/sfx071"},{"key":"ref070","unstructured":"ParisiM. and GlassI. (2017) Joubert Syndrome, 2003 Jul 9 [Updated 2017 Jun 29]. In: M.Adam, H.H. Ardinger, R.A. Pagon, et al., editors. GeneReviews\n                      \u00ae\n                      [Internet]. Seattle (WA): University of Washington, Seattle; 1993\u20132019."},{"key":"ref071","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30229"},{"key":"ref072","doi-asserted-by":"publisher","DOI":"10.1086\/421846"},{"key":"ref073","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201648"},{"key":"ref074","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.036608"},{"key":"ref075","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.94"},{"key":"ref076","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1249630"},{"key":"ref077","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2016-104425"},{"key":"ref078","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000884"},{"key":"ref079","doi-asserted-by":"publisher","DOI":"10.1038\/ng.826"},{"key":"ref080","doi-asserted-by":"publisher","DOI":"10.1002\/uog.12567"},{"key":"ref081","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809432115"},{"key":"ref082","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.60"},{"key":"ref083","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-9-72"},{"key":"ref084","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2016-103832"},{"key":"ref085","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-016-1689-z"},{"key":"ref086","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0858-z"},{"key":"ref087","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.04.019"},{"key":"ref088","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19991029)86:5<459::AID-AJMG12>3.0.CO;2-C"},{"key":"ref089","doi-asserted-by":"publisher","DOI":"10.1086\/302819"},{"key":"ref090","doi-asserted-by":"publisher","DOI":"10.1038\/ng1786"},{"key":"ref091","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101284"},{"key":"ref092","first-page":"3","volume":"16","author":"Senocak E.U.","year":"2010","journal-title":"Diagn Interv Radiol"},{"key":"ref093","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv242"},{"key":"ref094","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21507"},{"key":"ref095","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu555"},{"key":"ref096","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.11.010"},{"key":"ref097","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-1099-5"},{"key":"ref098","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2015-103250"},{"key":"ref099","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2017.00287"},{"key":"ref100","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.09.009"},{"key":"ref101","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101132"},{"key":"ref102","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.02.011"},{"key":"ref103","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-973701"},{"key":"ref104","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000001816"},{"key":"ref105","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38272"},{"key":"ref106","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12836"},{"key":"ref107","author":"Thomas S.","year":"2014","journal-title":"Eur J Hum Genet"},{"key":"ref108","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.06.017"},{"key":"ref109","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22470"},{"key":"ref110","unstructured":"TorielloH.V., FrancoB., BruelA.L. and Thauvin-RobinetC., Oral-Facial-Digital Syndrome Type I, 2002 Jul 24 [Updated 2016 Aug 4]. In: M.P. Adam, H.H. Ardinger, R.A. Pagon, et al., editors. GeneReviews\n                      \u00ae\n                      [Internet]. Seattle (WA): University of Washington, Seattle; 1993\u20132019."},{"key":"ref111","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2006101164"},{"key":"ref112","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.11.019"},{"key":"ref113","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-005-2054-y"},{"key":"ref114","doi-asserted-by":"publisher","DOI":"10.1038\/ng.594"},{"key":"ref115","doi-asserted-by":"publisher","DOI":"10.1038\/ng1805"},{"key":"ref116","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.05.010"},{"key":"ref117","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320320217"},{"key":"ref118","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.204"},{"key":"ref119","doi-asserted-by":"publisher","DOI":"10.3390\/genes9120605"},{"key":"ref120","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3201"},{"key":"ref121","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002630"}],"container-title":["Translational Science of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3233\/TRD-190041","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.3233\/TRD-190041","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3233\/TRD-190041","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:21:22Z","timestamp":1777612882000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.3233\/TRD-190041"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,4]]},"references-count":121,"journal-issue":{"issue":"1-2","published-print":{"date-parts":[[2019,7,4]]}},"alternative-id":["10.3233\/TRD-190041"],"URL":"https:\/\/doi.org\/10.3233\/trd-190041","relation":{},"ISSN":["2214-6490","2214-6512"],"issn-type":[{"value":"2214-6490","type":"print"},{"value":"2214-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,4]]}}}