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.

Figure 1

Distribution of Individuals with JBTS in the Lower St. Lawrence Region Numbers refer to families (pedigrees in Figure 2). Note the cluster of families along Route 132, which follows the Matapedia River.

Figure 2

Segregation of C5ORF42 Mutations in Families Affected by JBTS

Figure 3

C5ORF42 Mutations Identified in Individuals with JBTS (A) Scheme showing the positions of the mutations with respect to the different C5ORF42 Ensembl-annotated transcripts that are predicted to produce proteins. The numbering on top is based on the cDNA positions of ENST00000425232 (identical to RefSeq accession number NM_023073.3). Mutation c.7957+288G>A is annotated as part of a coding exon in ENST00000388739 and causes a missense change (p.Ala1564Thr). (B) NCBI HomoloGene-generated amino acid alignment of C5ORF42. Its predicted orthologs show the conservation of the Arg1336 residue.