Characterization of three ciliopathy pedigrees expands the phenotype associated with biallelic C2CD3 variants

Abstract

Whole exome sequencing (WES) is utilized in diagnostic odyssey cases to identify the underlying genetic cause associated with complex phenotypes. Recent publications suggest that WES reveals the genetic cause in ~25% of these cases and is most successful when applied to children with neurological disease. The residual 75% of cases remain genetically elusive until more information becomes available in the literature or functional studies are pursued. WES performed on three families with presumed ciliopathy diagnoses, including orofaciodigital (OFD) syndrome, fetal encephalocele, or Joubert-related disorder, identified compound heterozygous variants in C2CD3. Biallelic variants in C2CD3 have previously been associated with ciliopathies, including OFD syndrome type 14 (OFD14; MIM: 615948). As three of the six identified variants were predicted to affect splicing, exon-skipping analysis using either RNA sequencing or PCR-based methods were completed to determine the pathogenicity of these variants, and showed that each of the splicing variants led to a frameshifted protein product. Using these studies in combination with the 2015 ACMG guidelines, each of the six identified variants were classified as either pathogenic or likely pathogenic, and are therefore likely responsible for our patients' phenotypes. Each of the families had a distinct clinical phenotype and severity of disease, extending from lethal to viable. These findings highlight that there is a broad phenotypic spectrum associated with C2CD3-mediated disease and not all patients present with the typical features of OFD14.

CEP120 interacts with C2CD3 and Talpid3 and is required for centriole appendage assembly and ciliogenesis

“…Finally, recent reports showed that mutations in the C2CD3 gene cause skeletal dysplasia, polydactyly, and ciliopathies 50,51 , while Talpid3 mutations cause Joubert syndromes and Short-Rib polydactyly syndromes 52,53 . We herein showed that CEP120 directly interacts with C2CD3 (Fig.…”

Mutation in the Ciliary Protein C2CD3 Reveals Organ-Specific Mechanisms of Hedgehog Signal Transduction in Avian Embryos

“…The ta 3 has a more severe DV patterning defect (a complete loss of ventral cell types) in the neural tube than the ta 2 [71]. While the ta 2 phenocopies craniofacial phenotypes associated with Oral-facial-digital syndrome subtype 14 (OFD14) [47,[95][96][97], the ta 3 presents with craniofacial phenotypes associated with Joubert syndrome including hypertelorism and hypoplastic jaws [98][99][100][101][102]. While the ta 2 and ta 3 GI tracts are both significantly shorter than control embryos, the intestinal ENS phenotypes are divergent from each other as the ta 2 hindgut has an increased number of ENCCs whereas ta 3 guts have reduced numbers of ENCCs [103,104].…”

“…For example, Hh signaling is required to properly pattern the dorsalventral axis of the somite that subsequently allows for differentiation into the dermatome (presumptive skin), myotome (presumptive muscle), and the sclerotome (presumptive vertebrae) [107][108][109][110]. Interestingly, previous studies reported that the ta 2 embryo presents with mispatterned muscles and a shortened vertebral column [42,48] and human patients that present with OFD14 possess musculoskeletal anomalies [96,97]. Future work with the ta 2 embryo will assess if and how these particular phenotypes arise due to perturbations in cilia-dependent Hh signaling.…”

Synergistic Genetic Interactions between Pkhd1 and Pkd1 Result in an ARPKD-Like Phenotype in Murine Models

“…79 We also observed dysregulation of several known ciliopathy genes, Jbts17, 80 Cep164, 81 Cep250, 82 Sclt1, 83 Ift140, 84 and C2cd3. 85,86 Additionally, Dzip1l, which is associated with an ARPKD-like phenotype in humans and mice by altering PC1/PC2 ciliary localization, 87 showed a significant increase in gene expression.…”