Article Text
Abstract
Purpose In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A.
Methods We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature.
Results Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype–phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype.
Conclusion This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.
- phenotype
- genotype
- cerebellar diseases
- genetic testing
- nervous system malformations
Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study.
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Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study.
Footnotes
SV and LB contributed equally.
Contributors The corresponding author MH contributed to the planning, reporting, conception, data acquisition, organising, and interpretation; statistical analysis; graphic figures designing; drafting and correcting of this original research. LQ contributed in data acquisition and interpretation as well as the revising of the work. LB and SV contributed equally to the conducting, planning, conception and interpretation of data as well as the revising of this article. LB is guarantor of this work. DR contributed in the planning, conducting, data acquisition and revising of this work. CG participated in the analysis of data; in particular she interpreted the brain MRIs. She also participated in revising the work. AR, CR and AA helped in data acquisition, conceptualisation of the work, interpretation of data and revising of the document. ML helped in data acquisition and interpretation as well as the revising of the work. EL contributed to the acquisition and interpretation of the neuropsychological tests of patients as well as the revising of the work. OL contributed to the statistical analysis using Julia software and revising of the document. The rest of the authors contributed to data acquisitions as well as revising of the final work.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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