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A molecular genetic study of autism and related phenotypes in extended pedigrees

BACKGROUND: Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for i...

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Autores principales: Piven, Joseph, Vieland, Veronica J, Parlier, Morgan, Thompson, Ann, O’Conner, Irene, Woodbury-Smith, Mark, Huang, Yungui, Walters, Kimberly A, Fernandez, Bridget, Szatmari, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851306/
https://www.ncbi.nlm.nih.gov/pubmed/24093601
http://dx.doi.org/10.1186/1866-1955-5-30
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author Piven, Joseph
Vieland, Veronica J
Parlier, Morgan
Thompson, Ann
O’Conner, Irene
Woodbury-Smith, Mark
Huang, Yungui
Walters, Kimberly A
Fernandez, Bridget
Szatmari, Peter
author_facet Piven, Joseph
Vieland, Veronica J
Parlier, Morgan
Thompson, Ann
O’Conner, Irene
Woodbury-Smith, Mark
Huang, Yungui
Walters, Kimberly A
Fernandez, Bridget
Szatmari, Peter
author_sort Piven, Joseph
collection PubMed
description BACKGROUND: Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD. METHODS: We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior. RESULTS: Results reveal substantial between-family locus heterogeneity and support the importance of previously reported ASD loci in inherited, familial, forms of ASD. Additional loci, not seen in the ASD analyses, show evidence for linkage to the broad autism phenotype (BAP). BAP peaks are well supported by multiple subphenotypes (including anxiety, pragmatic language, and social behavior) showing linkage to regions overlapping with the compound BAP phenotype. Whereas 'repetitive behavior’, showing the strongest evidence for linkage (Posterior Probability of Linkage = 62% at 6p25.2-24.3, and 69% at 19p13.3), appears to be linked to novel regions not detected with other compound or narrow phenotypes examined in this study. CONCLUSIONS: These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears to correspond to sets of subclinical features segregating with ASD within pedigrees, and that different features of the ASD phenotype segregate independently of one another. These findings support the additional study of larger, even more individually informative pedigrees, together with measurement of multiple, behavioral- and biomarker-based phenotypes, in both affected and non-affected individuals, to elucidate the complex genetics of familial ASD.
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spelling pubmed-38513062013-12-06 A molecular genetic study of autism and related phenotypes in extended pedigrees Piven, Joseph Vieland, Veronica J Parlier, Morgan Thompson, Ann O’Conner, Irene Woodbury-Smith, Mark Huang, Yungui Walters, Kimberly A Fernandez, Bridget Szatmari, Peter J Neurodev Disord Research BACKGROUND: Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD. METHODS: We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior. RESULTS: Results reveal substantial between-family locus heterogeneity and support the importance of previously reported ASD loci in inherited, familial, forms of ASD. Additional loci, not seen in the ASD analyses, show evidence for linkage to the broad autism phenotype (BAP). BAP peaks are well supported by multiple subphenotypes (including anxiety, pragmatic language, and social behavior) showing linkage to regions overlapping with the compound BAP phenotype. Whereas 'repetitive behavior’, showing the strongest evidence for linkage (Posterior Probability of Linkage = 62% at 6p25.2-24.3, and 69% at 19p13.3), appears to be linked to novel regions not detected with other compound or narrow phenotypes examined in this study. CONCLUSIONS: These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears to correspond to sets of subclinical features segregating with ASD within pedigrees, and that different features of the ASD phenotype segregate independently of one another. These findings support the additional study of larger, even more individually informative pedigrees, together with measurement of multiple, behavioral- and biomarker-based phenotypes, in both affected and non-affected individuals, to elucidate the complex genetics of familial ASD. BioMed Central 2013 2013-10-05 /pmc/articles/PMC3851306/ /pubmed/24093601 http://dx.doi.org/10.1186/1866-1955-5-30 Text en Copyright © 2013 Piven et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Piven, Joseph
Vieland, Veronica J
Parlier, Morgan
Thompson, Ann
O’Conner, Irene
Woodbury-Smith, Mark
Huang, Yungui
Walters, Kimberly A
Fernandez, Bridget
Szatmari, Peter
A molecular genetic study of autism and related phenotypes in extended pedigrees
title A molecular genetic study of autism and related phenotypes in extended pedigrees
title_full A molecular genetic study of autism and related phenotypes in extended pedigrees
title_fullStr A molecular genetic study of autism and related phenotypes in extended pedigrees
title_full_unstemmed A molecular genetic study of autism and related phenotypes in extended pedigrees
title_short A molecular genetic study of autism and related phenotypes in extended pedigrees
title_sort molecular genetic study of autism and related phenotypes in extended pedigrees
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851306/
https://www.ncbi.nlm.nih.gov/pubmed/24093601
http://dx.doi.org/10.1186/1866-1955-5-30
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