title: Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population.
abstract: Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs*31], c.4804C>T [p.Arg1602*], and c.7477C>T [p.Arg2493*]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS.
authors.affiliation: Centre of Excellence in Neurosciences, Université de Montréal and Sainte-Justine Hospital Research Center, Montréal, QC, Canada.
authors.forename: Myriam
authors.initials: M
authors.lastname: Srour
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.forename: Luis H
authors.initials: LH
authors.lastname: Ospina
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.forename: Damian
authors.initials: D
authors.lastname: Labuda
authors.forename: Christine
authors.initials: C
authors.lastname: Massicotte
authors.forename: Sylvia
authors.initials: S
authors.lastname: Dobrzeniecka
authors.forename: José-Mario
authors.initials: JM
authors.lastname: Capo-Chichi
authors.forename: Simon
authors.initials: S
authors.lastname: Papillon-Cavanagh
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Michael I
authors.initials: MI
authors.lastname: Shevell
authors.forename: Rachel
authors.initials: R
authors.lastname: Laframboise
authors.forename: Valérie
authors.initials: V
authors.lastname: Désilets
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
mesh_terms: D000015:Abnormalities, Multiple; D000328:Adult; D001483:Base Sequence; D002170:Canada; D002526:Cerebellar Diseases / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000002:abnormalities
chemical_list: C572460:CPLANE1 protein, human; D008565:Membrane Proteins