title: Joubert Syndrome in French Canadians and Identification of Mutations in CEP104.
abstract: Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1A4, Canada.
authors.forename: Myriam
authors.initials: M
authors.lastname: Srour
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Dianalee
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authors.lastname: McKnight
authors.affiliation: Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Davis
authors.affiliation: Metabolic Unit, Department of Pediatrics, Rambam Health Care Campus, Haifa 3109601, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 1A4, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Brissa
authors.initials: B
authors.lastname: Martin
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Nassif
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC H3H 2B4, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dionne-Laporte
authors.affiliation: Department of Ophthalmology, Sainte-Justine Hospital, Montreal, QC H3T 1C5, Canada.
authors.forename: Luis H
authors.initials: LH
authors.lastname: Ospina
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Lemyre
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Massicotte
authors.affiliation: Division of Medical Genetics, Centre Hospitalier Universitaire de Québec, Quebec City, QC G1V 4G2, Canada.
authors.forename: Rachel
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authors.lastname: Laframboise
authors.affiliation: Division of Medical Genetics, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
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authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Damian
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authors.lastname: Labuda
authors.affiliation: Department of Medical Imaging, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Décarie
authors.affiliation: Department of Medical Imaging, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Françoise
authors.initials: F
authors.lastname: Rypens
authors.affiliation: MRI Unit, Rambam Medical Center, Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa 3109601, Israel.
authors.forename: Dorith
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authors.lastname: Goldsher
authors.affiliation: Department of Pathology, Sainte-Justine Hospital, Montreal, QC H3T 1C5, Canada.
authors.forename: Catherine
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authors.lastname: Fallet-Bianco
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Soucy
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Laberge
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
authors.forename: Catalina
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authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
authors.forename: Kym
authors.initials: K
authors.lastname: Boycott
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1A4, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
authors.affiliation: Division of Neurology, Centre Hospitalier Universitaire de Québec, Quebec City, QC G1V 4G2, Canada.
authors.forename: Renée-Myriam
authors.initials: RM
authors.lastname: Boucher
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1A4, Canada; Montreal Neurological Institute, McGill University, Montreal, QC H3H 2B4, Canada; Department of Human Genetics, McGill University, Montreal, QC H3H 2B4, Canada.
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authors.initials: GA
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authors.affiliation: Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27710, USA.
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authors.affiliation: McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 1A4, Canada.
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authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
authors.forename: Orly
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authors.lastname: Elpeleg
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authors.forename: Mary K
authors.initials: MK
authors.lastname: Kukolich
authors.affiliation: Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa 3525433, Israel. Electronic address: stavit_sh@clalit.org.il.
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.affiliation: Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T 1J4, Canada. Electronic address: jacques.michaud@recherche-ste-justine.qc.ca.
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mesh_terms: D000015:Abnormalities, Multiple / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D002170:Canada / Q000453:epidemiology; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000378:metabolism / Q000473:pathology*; D059472:Exome / Q000235:genetics; D005124:Eye Abnormalities / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D052177:Kidney Diseases, Cystic / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011379:Prognosis; D012160:Retina / Q000002:abnormalities* / Q000473:pathology; D055815:Young Adult
chemical_list: D008869:Microtubule-Associated Proteins