Joubert Syndrome via the CPLANE1 (C5orf42) Gene

Joubert Syndrome (JBTS; OMIM 614615) is an autosomal recessive condition marked by mid-hindbrain malformation, retinal dystrophy, cystic renal disease, hepatic fibrosis and polydactyly (Doherty, 2009). Mid-hindbrain malformation, which can be readily identified as a “Molar Tooth Sign” (MTS) using Magnetic Resonance Imaging (MRI), typically leads to hypotonia, ataxia, abnormal eye movements and intellectual disability; MTS is pathognomonic for JBTS.

JBTS is known to be caused by at least 18 different genes (see GeneReviews, www.ncbi.nlm.nih.gov/projects/GeneTests). Mutations in CPLANE1 (C5ORF42) were identified in a cohort of 7 unrelated French Canadian families with classic features of JBTS (Srour et al. 2012). Interestingly, this cohort included the original JBTS family, first described by Marie Joubert in 1969, for which the molecular cause had remained elusive until this report. Three different mutations (c.4006C>T [p.Arg1336Trp], c.7400+1G>A, and c.4690G>A [p.Ala1564Thr]) were found in multiple individuals indicating that CPLANE1 is associated with a complex founder effect in the French Canadian population (Srour et al. 2012). The c.4690G>A variant, which we define as c.7957+288G>A according to HGVS convention, is located in the intron between exons 40 and 41 of the longest RefSeq isoform (NM_023073.3). Upon further inspection, Srour et al. (2012) concluded that this variant is located within an alternatively spliced exon (40b) and predicted to result in a missense change (Ala to Thr). Four affected individuals carried this c.4690G>A variant, in addition to one of three other mutations (c.7400+1G>A, Arg2493* or Arg1336Trp). Therefore, the authors conclude that the c.4690G>A variant is probably pathogenic, although it is possibly benign and linked to an undetected pathogenic mutation. Future work is still need to assess the pathogenicity of this variant. The major CPLANE1 isoform (NM_023073.3) is predicted to have 51 exons, and the protein is thought to consist of 3,198 amino acids. Very little is known about the C5ORF5 protein, although given the role of other JBTS proteins it is likely a component of the primary cilium.

For French Canadian patients, the clinical sensitivity is predicted to be ~50% (Srour et al. 2012). For all other JBTS patients, the sensitivity is likely <1%.

This test provides full coverage of all coding exons of the CPLANE1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).