TY - JOUR
T1 - Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center
AU - NISC Comparative Sequencing Program
AU - Summers, Angela C.
AU - Snow, Joseph
AU - Wiggs, Edythe
AU - Liu, Alexander G.
AU - Toro, Camilo
AU - Poretti, Andrea
AU - Zein, Wadih M.
AU - Brooks, Brian P.
AU - Parisi, Melissa A.
AU - Inati, Sara
AU - Doherty, Dan
AU - Vemulapalli, Meghana
AU - Mullikin, Jim C.
AU - Vilboux, Thierry
AU - Gahl, William A.
AU - Gunay-Aygun, Meral
N1 - Funding Information:
The authors thank the Joubert syndrome and Related Disorders Foundation for their extensive support and the individuals with JS and their families who generously participated in this investigation. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, (NHGRI) and by the National Institute of Mental Health (NIMH), and NIH Clinical Center, National Institutes of Health (NIH), Bethesda, Maryland. The authors have no conflicts of interest relevant to this article to disclose. Angela Summers conceptualized the neuropsychological data analysis, prepared figures, drafted the initial manuscript, and approved the final manuscript as submitted. Dr. Joseph Snow designed the neuropsychological data collection, conceptualized the analysis and interpretation, critically revised the manuscript, and approved the final manuscript as submitted. Dr. Edythe Wiggs was involved in the neuropsychological data collection, revised the manuscript, and approved the final manuscript as submitted. Alex Liu assisted with neuropsychological data collection and tabulation, revised the manuscript, and approved the final manuscript as submitted. Dr. Camilo Toro performed neurological examinations, conceptualized the data analysis, revised the manuscript, and approved the final manuscript as submitted. Dr. Andrea Poretti conceptualized the brain MRI data collection, re-evaluated and scored brain MRI images, analyzed the brain imaging data, revised the manuscript, and approved the final manuscript as submitted. Dr. Wadih Zein and Dr. Brian Brooks performed eye examinations, analyzed and interpreted the eye findings, revised the manuscript, and approved the final manuscript as submitted. Dr. Melissa Parisi participated in participant recruitment, conceptualized the data analysis, assisted in data interpretation, critically revised the manuscript, and approved the final manuscript as submitted. Dr. Sara Inati interpreted electroencephalography data, revised the manuscript, and approved the final manuscript as submitted. Dr. Dan Doherty participated in participant recruitment, interpreted Molecular Inversion Probes DNA sequencing, assisted in data interpretation, critically revised the manuscript, and approved the final manuscript as submitted. Meghana Vemulapalli, Jim C. Mullikin, and the NISC Comparative Sequencing Program performed whole exome sequencing. Thierry Vilboux interpreted whole exome data, revised the manuscript, and approved the final manuscript as submitted. Dr. William A. Gahl, financially accountable investigator of the study, critically reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Meral Gunay-Aygun, principal investigator of the clinical trial, designed the study, recruited the participants, performed clinical evaluations, established collaborations, analyzed clinical and molecular data, conceptualized the neuropsychological data analysis and interpretation, revised the manuscript, and approved the final manuscript as submitted.
Funding Information:
The authors thank the Joubert syndrome and Related Disorders Foundation for their extensive support and the individuals with JS and their families who generously participated in this investigation. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, (NHGRI) and by the National Institute of Mental Health (NIMH), and NIH Clinical Center, National Institutes of Health (NIH), Bethesda, Maryland.
Publisher Copyright:
© 2017 Wiley Periodicals, Inc.
PY - 2017/7
Y1 - 2017/7
N2 - 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.
AB - 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.
KW - EEG
KW - JSRD
KW - Joubert syndrome
KW - MRI
KW - cognition
KW - neuropsychological function
UR - http://www.scopus.com/inward/record.url?scp=85018926834&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018926834&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.38272
DO - 10.1002/ajmg.a.38272
M3 - Article
C2 - 28497568
AN - SCOPUS:85018926834
SN - 1552-4825
VL - 173
SP - 1796
EP - 1812
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 7
ER -