Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly
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 t...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-11-01
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| Series: | Molecular Autism |
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| Online Access: | http://link.springer.com/article/10.1186/s13229-017-0175-3 |
| _version_ | 1828355849664331776 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Marc Woodbury-Smith |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T02:49:53Z |
| format | Article |
| id | doaj.art-3dd659a3beed43c69f876cdfc1032c2d |
| institution | Directory Open Access Journal |
| issn | 2040-2392 |
| language | English |
| last_indexed | 2024-04-14T02:49:53Z |
| publishDate | 2017-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Autism |
| spelling | doaj.art-3dd659a3beed43c69f876cdfc1032c2d2022-12-22T02:16:20ZengBMCMolecular Autism2040-23922017-11-018111010.1186/s13229-017-0175-3Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephalyMarc Woodbury-Smith0Eric Deneault1Ryan K. C. Yuen2Susan Walker3Mehdi Zarrei4Giovanna Pellecchia5Jennifer L. Howe6Ny Hoang7Mohammed Uddin8Christian R. Marshall9Christina Chrysler10Ann Thompson11Peter Szatmari12Stephen W. Scherer13Institute of Neuroscience, Newcastle University, c/o Sir James Spence InstituteProgram in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick ChildrenProgram in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick ChildrenAutism Research Unit, The Hospital for Sick ChildrenMohammed Bin Rashid University of Medicine and Health SciencesProgram in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick ChildrenDepartment of Psychiatry and Behavioural Neurosciences, McMaster UniversityDepartment of Psychiatry and Behavioural Neurosciences, McMaster UniversityCentre for Addiction and Mental Health, The Hospital for Sick Children and University of TorontoProgram in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick ChildrenAbstract 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.http://link.springer.com/article/10.1186/s13229-017-0175-3RAB39BIntellectual disability (ID)RNAseqWhole genome sequencing (WGS) |
| spellingShingle | 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 Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly Molecular Autism RAB39B Intellectual disability (ID) RNAseq Whole genome sequencing (WGS) |
| title | Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly |
| title_full | Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly |
| title_fullStr | Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly |
| title_full_unstemmed | Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly |
| title_short | Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly |
| title_sort | mutations in rab39b in individuals with intellectual disability autism spectrum disorder and macrocephaly |
| topic | RAB39B Intellectual disability (ID) RNAseq Whole genome sequencing (WGS) |
| url | http://link.springer.com/article/10.1186/s13229-017-0175-3 |
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