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Cohort Expansion and Genotype-Phenotype Analysis of RAB11A-Associated Neurodevelopmental Disorder.
- Source :
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Pediatric neurology [Pediatr Neurol] 2024 Nov; Vol. 160, pp. 45-53. Date of Electronic Publication: 2024 Jul 20. - Publication Year :
- 2024
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Abstract
- Background: GTPases of the Rab family are important orchestrators of membrane trafficking, and their dysregulation has been linked to a variety of neuropathologies. In 2017, we established a causal link between RAB11A variants and developmental and epileptic encephalopathy. In this study, we expand the phenotype of RAB11A-associated neurodevelopmental disorder and explore genotype-phenotype correlations.<br />Methods: We assessed 16 patients with pathogenic or likely pathogenic RAB11A variants, generally de novo, heterozygous missense variants. One individual had a homozygous nonsense variant, although concomitant with a pathogenic LAMA2 variant, which made their respective contributions to the phenotype difficult to discriminate.<br />Results: We reinforce the finding that certain RAB11A missense variants lead to intellectual disability and developmental delays. Other clinical features might include gait disturbances, hypotonia, magnetic resonance imaging abnormalities, visual anomalies, dysmorphisms, early adrenarche, and obesity. Epilepsy seems to be less common and linked to variants outside the binding sites. Individuals with variants in the binding sites seem to have a more multisystemic, nonepileptic phenotype.<br />Conclusions: Similar to other Rab-related disorders, RAB11A-associated neurodevelopmental disorder can also impact gait, tonus, brain anatomy and physiology, vision, adrenarche, and body weight and structure. Epilepsy seems to affect the minority of patients with variants outside the binding sites.<br />Competing Interests: Declaration of competing interest The Department of Molecular & Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. Sureni V. Mullegama is an employee of GeneDx, LLC. Otherwise, we have no conflict of interest to disclose.<br /> (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Male
Child
Female
Child, Preschool
Adolescent
Cohort Studies
Mutation, Missense
Phenotype
Intellectual Disability genetics
Intellectual Disability diagnostic imaging
Epilepsy genetics
Epilepsy physiopathology
Epilepsy diagnostic imaging
Infant
Developmental Disabilities genetics
Developmental Disabilities diagnostic imaging
Developmental Disabilities etiology
rab GTP-Binding Proteins genetics
Neurodevelopmental Disorders genetics
Genetic Association Studies
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5150
- Volume :
- 160
- Database :
- MEDLINE
- Journal :
- Pediatric neurology
- Publication Type :
- Academic Journal
- Accession number :
- 39181022
- Full Text :
- https://doi.org/10.1016/j.pediatrneurol.2024.07.010