2. Academic Validation
  3. Joubert Syndrome in French Canadians and Identification of Mutations in CEP104

Joubert Syndrome in French Canadians and Identification of Mutations in CEP104

  • Am J Hum Genet. 2015 Nov 5;97(5):744-53. doi: 10.1016/j.ajhg.2015.09.009.
Myriam Srour 1,  Fadi F Hamdan 2,  Dianalee McKnight 3,  Erica Davis 4,  Hanna Mandel 5,  Jeremy Schwartzentruber 6,  Brissa Martin 3,  Lysanne Patry 2,  Christina Nassif 2,  Alexandre Dionne-Laporte 7,  Luis H Ospina 8,  Emmanuelle Lemyre 2,  Christine Massicotte 2,  Rachel Laframboise 9,  Bruno Maranda 10,  Damian Labuda 2,  Jean-Claude Décarie 11,  Françoise Rypens 11,  Dorith Goldsher 12,  Catherine Fallet-Bianco 13,  Jean-François Soucy 2,  Anne-Marie Laberge 2,  Catalina Maftei 2,  Care4Rare Canada Consortium,  Kym Boycott 14,  Bernard Brais 15,  Renée-Myriam Boucher 16,  Guy A Rouleau 17,  Nicholas Katsanis 4,  Jacek Majewski 6,  Orly Elpeleg 18,  Mary K Kukolich 19,  Stavit Shalev 20,  Jacques L Michaud 21
Affiliations

Affiliations

  • 1 Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1A4, Canada.
  • 2 Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
  • 3 GeneDx, Gaithersburg, MD 20877, USA.
  • 4 Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27710, USA.
  • 5 Metabolic Unit, Department of Pediatrics, Rambam Health Care Campus, Haifa 3109601, Israel.
  • 6 McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 1A4, Canada.
  • 7 Montreal Neurological Institute, McGill University, Montreal, QC H3H 2B4, Canada.
  • 8 Department of Ophthalmology, Sainte-Justine Hospital, Montreal, QC H3T 1C5, Canada.
  • 9 Division of Medical Genetics, Centre Hospitalier Universitaire de Québec, Quebec City, QC G1V 4G2, Canada.
  • 10 Division of Medical Genetics, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
  • 11 Department of Medical Imaging, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada.
  • 12 MRI Unit, Rambam Medical Center, Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa 3109601, Israel.
  • 13 Department of Pathology, Sainte-Justine Hospital, Montreal, QC H3T 1C5, Canada.
  • 14 Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
  • 15 Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 1A4, Canada.
  • 16 Division of Neurology, Centre Hospitalier Universitaire de Québec, Quebec City, QC G1V 4G2, Canada.
  • 17 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.
  • 18 Monique and Jacques Roboh Department of Genetic Research, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
  • 19 Cook Children's Medical Center, Fort Worth, TX 76104, USA.
  • 20 Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa 3525433, Israel. Electronic address: stavit_sh@clalit.org.il.
  • 21 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.
PMID: 26477546 DOI: 10.1016/j.ajhg.2015.09.009
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.

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