{"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":1792643837279,"version":"4.5.0"},"reference-count":48,"publisher":"BMJ","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2011,12,8]]},"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Joubert syndrome (JS) is a ciliopathy characterised by a distinctive brain malformation (the \u2018molar tooth sign\u2019), developmental delay, abnormal eye movements and abnormal breathing pattern. Retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly are variably present, resulting in significant phenotypic heterogeneity and overlap with other ciliopathies. JS is also genetically heterogeneous, resulting from mutations in 13 genes. These factors render clinical\/molecular diagnosis and management challenging. <jats:italic>CC2D2A<\/jats:italic> mutations are a relatively common cause of JS and also cause Meckel syndrome. The clinical consequences of <jats:italic>CC2D2A<\/jats:italic> mutations in patients with JS have been incompletely reported.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Subjects with JS from 209 families were evaluated to identify mutations in <jats:italic>CC2D2A<\/jats:italic>. Clinical and imaging features in subjects with <jats:italic>CC2D2A<\/jats:italic> mutations were compared with those in subjects without <jats:italic>CC2D2A<\/jats:italic> mutations and reports in the literature.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>10 novel <jats:italic>CC2D2A<\/jats:italic> mutations in 20 subjects were identified; a summary is provided of all published <jats:italic>CC2D2A<\/jats:italic> mutations. Subjects with <jats:italic>CC2D2A<\/jats:italic>-related JS were more likely to have ventriculomegaly (p&lt;0.0001) and seizures (p=0.024) than subjects without <jats:italic>CC2D2A<\/jats:italic> mutations. No mutation-specific genotype\u2013phenotype correlations could be identified, but the findings confirm the observation that mutations that cause <jats:italic>CC2D2A<\/jats:italic>-related JS are predicted to be less deleterious than mutations that cause <jats:italic>CC2D2A<\/jats:italic>-related Meckel syndrome. Missense variants in the coiled-coil and C2 domains, as well as the C-terminal region, identify these regions as important for the biological mechanisms underlying JS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                     <jats:italic>CC2D2A<\/jats:italic> testing should be prioritised in patients with JS and ventriculomegaly and\/or seizures. Patients with <jats:italic>CC2D2A<\/jats:italic>-related JS should be monitored for hydrocephalus and seizures.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2011-100552","type":"journal-article","created":{"date-parts":[[2012,1,12]],"date-time":"2012-01-12T21:03:29Z","timestamp":1326402209000},"page":"126-137","source":"Crossref","is-referenced-by-count":67,"title":["Genotype\u2013phenotype correlation in <i>CC2D2A<\/i>-related Joubert syndrome reveals an association with ventriculomegaly and seizures"],"prefix":"10.1136","volume":"49","author":[{"given":"Ruxandra","family":"Bachmann-Gagescu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisele E","family":"Ishak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer C","family":"Dempsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Adkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"O'Day","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian G","family":"Phelps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meral","family":"Gunay-Aygun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonie D","family":"Kline","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Szczaluba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loreto","family":"Martorell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulrahman","family":"Alswaid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shatha","family":"Alrasheed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashidhar","family":"Pai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Izatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Ronan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A","family":"Parisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Mefford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Glass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Doherty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2012,1,12]]},"reference":[{"key":"2025101714283691000_49.2.126.1","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1212\/WNL.19.9.813","article-title":"Familial agenesis of the cerebellar vermis. 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