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Am J Med Genet A. 2017 Jul;173(7):1796-1812. doi: 10.1002/ajmg.a.38272. Epub 2017 May 12.

Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center.

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Office of the Clinical Director, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Department of Psychology, Fordham University, Bronx, New York.
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland.
Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland.
Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
Intellectual and Developmental Disabilities Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Electroencephalography Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.
Department of Pediatrics, University of Washington, Seattle, Washington.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
Inova Translational Medicine Institute, Falls Church, Virginia.
Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
Department of Pediatrics and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.


Joubert syndrome (JS) is a genetically heterogeneous ciliopathy characterized by hypo-dysplasia of the cerebellar vermis, a distinct hindbrain/midbrain malformation (molar tooth sign), and intellectual disability. We evaluated the neuropsychological profiles of 76 participants with JS in the context of molecular genetics and clinical covariates. Evaluations included neuropsychological testing, structured parental interviews, DNA sequencing, brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination, and assessment for renal and hepatic disease. On average, participants manifested Full Scale Intelligence Quotients (FSIQ) in the moderately to profoundly low range (M = 64.3 ± 15.3). Of the Wechsler index scores, verbal comprehension was least affected and processing speed was most affected. Receptive language was rated as better than expressive language on the Vineland Adaptive Behavior Scales-Second Edition. Those with abnormal EEG had a significantly lower FSIQ (n = 15; M = 50.7 ± 12.9) compared to participants with normal EEG (n = 39; M = 64.7 ± 16.3; p = .004). Participants taking psychiatric medications manifested a lower FSIQ (n = 20; M = 54.8 ± 13.2) than those not taking them (n = 42; M = 65.0 ± 17.2; p = .022). These correlations were also present in the TMEM67-related JS sub-cohort (n = 14). Based on parental assessment, psychiatric and behavioral problems were significantly more common than in the general population for all measures (p < .004 for all). The majority (65%) of individuals with JS have some degree of intellectual disability. Abnormal EEG is associated with lower neuropsychological function. Processing speed is a weakness, while verbal comprehension and receptive language are relative strengths. These findings may guide parents, teachers, therapists, and doctors to determine appropriate therapies, accommodations, and academic goals for individuals with JS.


EEG; JSRD; Joubert syndrome; MRI; cognition; neuropsychological function

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