Submission Details

CPLANE1 was first reported in relation to autosomal recessive Joubert syndrome 17 in 2012 (Srour et al., PMID:22425360). Joubert syndrome 17 is caused by homozygous or compound heterozygous variants in CPLANE1 on chromosome 5p13.2 and is characterized by a distinctive congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis, referred to as the molar tooth sign (MTS). Additionally, these findings are accompanied by hypotonia, cerebellar ataxia, developmental delays, abnormal respiratory pattern, and/or oculomotor apraxia. CPLANE1 has been noted to be associated with the following disease entities: Orofaciodigital syndrome type IV and Joubert Syndrome 17. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Orofaciodigital syndrome was shown to be a very rare subtype of Joubert syndrome 17 characterized by the neurological features of JS associated with orofacial anomalies, mesoaxial or preaxial polydactyly, Y-shaped metacarpals, and hypothalamic hamartomas. Therefore, the following disease entities have been lumped into one disease entity, Joubert Syndrome 17 (OMIM:614615). At least 30 variants (missense, nonsense, frameshift, deletion, duplication, and splice site) have been reported in 21 probands across 4 publications (PMID: 22425360; Lopez et al., 2014, PMID: 24178751; Liu et al., 2020, PMID: 32233090; Zhang et al., 2021, PMID: 33822487) and included in this curation. The mechanism for disease has been noted to be loss of function, and it is suggested that at least one truncating mutation is needed to induce the phenotype. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by animal models, functional alteration studies, and rescue models. (Damerla et al., 2015, PMID: 25877302; Toriyama et al., 2016, PMID: 27158779). Mutant 'Hug' mice harboring a S253P variant at a highly conserved residue in the mouse homolog of CPLANE1 (2410089e03rik) were show to recapitulate phenotypes observed in Joubert syndrome 17 patients, including cleft lip/pallet, polydactyly, defects in the cerebellum, and cilia transition zone defects. Additionally, fibroblasts generated from an individual with Joubert syndrome with compound heterozygous JBTS17 variants demonstrated a lack of primary cilia formation compared to 90% ciliation in normal human fibroblast cells from a healthy control subject. Finally, full length WT-Jbts17 rescued the neural tube defects, ciliogenesis defects, and the loss of IFT-A basal body recruitment resulting from MO-based knockdown in Xenopus. In summary, there is definitive evidence to support the relationship between CPLANE1 and autosomal recessive Joubert Syndrome 17. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 12.17.2021 (SOP Version 8).