A genome-wide linkage study of autism spectrum disorder and the broad autism phenotype in extended pedigrees / M. WOODBURY-SMITH in Journal of Neurodevelopmental Disorders, 10-1 (December 2018)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 20 p. Titre : A genome-wide linkage study of autism spectrum disorder and the broad autism phenotype in extended pedigrees Type de document : Texte imprimé et/ou numérique Auteurs : M. WOODBURY-SMITH, Auteur ; Andrew D. PATERSON, Auteur ; I. O'CONNOR, Auteur ; M. ZARREI, Auteur ; R. K. C. YUEN, Auteur ; J. L. HOWE, Auteur ; A. THOMPSON, Auteur ; M. PARLIER, Auteur ; B. FERNANDEZ, Auteur ; J. PIVEN, Auteur ; Stephen SCHERER, Auteur ; V. VIELAND, Auteur ; P. SZATMARI, Auteur Année de publication : 2018 Article en page(s) : 20 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder (ASD)  Extended pedigrees  Family genetics  Genome-wide linkage  Posterior probability of linkage (PPL) Index. décimale : PER Périodiques Résumé : BACKGROUND: Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees. METHODS: ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale. RESULTS: The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent. CONCLUSIONS: Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity. En ligne : http://dx.doi.org/10.1186/s11689-018-9238-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386 [article] A genome-wide linkage study of autism spectrum disorder and the broad autism phenotype in extended pedigrees [Texte imprimé et/ou numérique] / M. WOODBURY-SMITH, Auteur ; Andrew D. PATERSON, Auteur ; I. O'CONNOR, Auteur ; M. ZARREI, Auteur ; R. K. C. YUEN, Auteur ; J. L. HOWE, Auteur ; A. THOMPSON, Auteur ; M. PARLIER, Auteur ; B. FERNANDEZ, Auteur ; J. PIVEN, Auteur ; Stephen SCHERER, Auteur ; V. VIELAND, Auteur ; P. SZATMARI, Auteur . - 2018 . - 20 p. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 20 p. Mots-clés : Autism spectrum disorder (ASD)  Extended pedigrees  Family genetics  Genome-wide linkage  Posterior probability of linkage (PPL) Index. décimale : PER Périodiques Résumé : BACKGROUND: Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees. METHODS: ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale. RESULTS: The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent. CONCLUSIONS: Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity. En ligne : http://dx.doi.org/10.1186/s11689-018-9238-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386

Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly / M. WOODBURY-SMITH in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 59p. Titre : Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly Type de document : Texte imprimé et/ou numérique Auteurs : M. WOODBURY-SMITH, Auteur ; E. DENEAULT, Auteur ; R. K. C. YUEN, Auteur ; S. WALKER, Auteur ; M. ZARREI, Auteur ; G. PELLECCHIA, Auteur ; J. L. HOWE, Auteur ; N. HOANG, Auteur ; M. UDDIN, Auteur ; C. R. MARSHALL, Auteur ; C. CHRYSLER, Auteur ; A. THOMPSON, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur Article en page(s) : 59p. Langues : Anglais (eng) Mots-clés : Intellectual disability (ID)  Rab39b  RNAseq  Whole genome sequencing (WGS) Index. décimale : PER Périodiques Résumé : 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. En ligne : http://dx.doi.org/10.1186/s13229-017-0175-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly [Texte imprimé et/ou numérique] / M. WOODBURY-SMITH, Auteur ; E. DENEAULT, Auteur ; R. K. C. YUEN, Auteur ; S. WALKER, Auteur ; M. ZARREI, Auteur ; G. PELLECCHIA, Auteur ; J. L. HOWE, Auteur ; N. HOANG, Auteur ; M. UDDIN, Auteur ; C. R. MARSHALL, Auteur ; C. CHRYSLER, Auteur ; A. THOMPSON, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur . - 59p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 59p. Mots-clés : Intellectual disability (ID)  Rab39b  RNAseq  Whole genome sequencing (WGS) Index. décimale : PER Périodiques Résumé : 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. En ligne : http://dx.doi.org/10.1186/s13229-017-0175-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

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