1. Mol Genet Genomic Med. 2021 Dec;9(12):e1603. doi: 10.1002/mgg3.1603. Epub 2021 
Jan 24.

Update of genetic variants in CEP120 and CC2D2A-With an emphasis on 
genotype-phenotype correlations, tissue specific transcripts and exploring 
mutation specific exon skipping therapies.

Barroso-Gil M(1), Olinger E(1), Ramsbottom SA(1), Molinari E(1), Miles CG(1), 
Sayer JA(1)(2)(3).

Author information:
(1)Translational and Clinical Research Institute, Faculty of Medical Sciences, 
Newcastle University, Newcastle Upon Tyne, UK.
(2)Renal Services, The Newcastle upon Tyne Hospitals NHS Foundation Trust, 
Newcastle Upon Tyne, UK.
(3)NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle 
Upon Tyne, UK.

BACKGROUND: Mutations in ciliary genes cause a spectrum of both overlapping and 
distinct clinical syndromes (ciliopathies). CEP120 and CC2D2A are paradigmatic 
examples for this genetic heterogeneity and pleiotropy as mutations in both 
cause Joubert syndrome but are also associated with skeletal ciliopathies and 
Meckel syndrome, respectively. The molecular basis for this phenotypical 
variability is not understood but basal exon skipping likely contributes to 
tolerance for deleterious mutations via tissue-specific preservation of the 
amount of expressed functional protein.
METHODS: We systematically reviewed and annotated genetic variants and clinical 
presentations reported in CEP120- and CC2D2A-associated disease and we combined 
in silico and ex vivo approaches to study tissue-specific transcripts and 
identify molecular targets for exon skipping.
RESULTS: We confirmed more severe clinical presentations associated with 
truncating CC2D2A mutations. We identified and confirmed basal exon skipping in 
the kidney, with possible relevance for organ-specific disease manifestations. 
Finally, we proposed a multimodal approach to classify exons amenable to exon 
skipping. By mapping reported variants, 14 truncating mutations in 7 CC2D2A 
exons were identified as potentially rescuable by targeted exon skipping, an 
approach that is already in clinical use for other inherited human diseases.
CONCLUSION: Genotype-phenotype correlations for CC2D2A support the 
deleteriousness of null alleles and CC2D2A, but not CEP120, offers potential for 
therapeutic exon skipping approaches.

© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley 
Periodicals LLC.

DOI: 10.1002/mgg3.1603
PMCID: PMC8683696
PMID: 33486889 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest.