Background Joubert syndrome is a clinically and genetically heterogeneous ciliopathy. Neuroimaging findings have not been systematically evaluated in a large cohort of patients with Joubert syndrome in correlation with molecular genetic cause and cognitive function.
Methods Brain MRI of 110 patients with Joubert syndrome was included in this study. A comprehensive evaluation of brain MRI studies for infratentorial and supratentorial morphological abnormalities was performed. Genetic cause was identified by whole-exome sequencing, and cognitive functions were assessed with age-appropriate neurocognitive tests in a subset of patients.
Results The cerebellar hemispheres were enlarged in 18% of the patients, mimicking macrocerebellum. The posterior fossa was enlarged in 42% of the patients, resembling Dandy-Walker malformation. Abnormalities of the brainstem, such as protuberance at the ventral contour of the midbrain, were present in 66% of the patients. Abnormalities of the supratentorial brain were present in approximately one-third of the patients, most commonly malrotation of the hippocampi. Mild ventriculomegaly, which typically did not require shunting, was present in 23% of the patients. No correlation between neuroimaging findings and molecular genetic cause was apparent. A novel predictor of outcome was identified; the more severe the degree of vermis hypoplasia, the worse the neurodevelopmental outcome was.
Conclusions The spectrum of neuroimaging findings in Joubert syndrome is wide. Neuroimaging does not predict the genetic cause, but may predict the neurodevelopmental outcome. A high degree of vermis hypoplasia correlates with worse neurodevelopmental outcome. This finding is important for prognostic counselling in Joubert syndrome.
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Contributors AP and MG-A conceptualised and designed the study, interpreted the results of the statistical analysis. AP drafted the manuscript. MG-A is the principal investigator of the NIH research protocol under which the patients were evaluated, recruited the patients, performed clinical evaluations, analysed clinical, molecular and imaging data, established collaborations. AP, AT, TAGMH, NA and MG-A evaluated the MR images. ACS and JS performed neurocognitive testing and interpretation of the neurocognitive data. KAC performed statistical analysis. CT performed neurological examinations and helped conceptualise the data analysis. MV, JCM and the NISC Comparative Sequencing Program performed whole-exome sequencing. TV interpreted whole-exome data. DY and ARC performed DNA sequencing for Sanger confirmation. DD assisted in recruiting patients and molecular genetic diagnosis. MAP assisted in conceptualising the study, recruited patients and assisted in interpretation of results. WAG is the financially accountable investigator of the NIH protocol; all co-authors critically revised the manuscript and read and approved the final manuscript.
Funding This research was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, Maryland, USA. KAC's work was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health through grant number 1UL1TR001079. DD's work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) through grant number R01NS064077 and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health through grant number U54HD083091 (Genetics Core and Sub-project 6849).
Competing interests None declared.
Patient consent Obtained.
Ethics approval This study has been approved by the National Human Genome Research Institute, NIH, Institutional Review Board and conducted in accordance with the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.
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