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Open Access 01-12-2017 | Research

Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly

Authors: Marc Woodbury-Smith, Eric Deneault, Ryan K. C. Yuen, Susan Walker, Mehdi Zarrei, Giovanna Pellecchia, Jennifer L. Howe, Ny Hoang, Mohammed Uddin, Christian R. Marshall, Christina Chrysler, Ann Thompson, Peter Szatmari, Stephen W. Scherer

Published in: Molecular Autism | Issue 1/2017

Abstract

Background

Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype.

Methods

Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses.

Results

Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis.

Conclusions

Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated.

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Title: Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly
Authors: Marc Woodbury-Smith
Eric Deneault
Ryan K. C. Yuen
Susan Walker
Mehdi Zarrei
Giovanna Pellecchia
Jennifer L. Howe
Ny Hoang
Mohammed Uddin
Christian R. Marshall
Christina Chrysler
Ann Thompson
Peter Szatmari
Stephen W. Scherer
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Molecular Autism / Issue 1/2017
Electronic ISSN: 2040-2392
DOI: https://doi.org/10.1186/s13229-017-0175-3

ACC 2024 Congress

Springer Medicine

Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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