Cargando…
A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome
Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9812786/ https://www.ncbi.nlm.nih.gov/pubmed/36192458 http://dx.doi.org/10.1038/s41380-022-01783-5 |
_version_ | 1784863807283134464 |
---|---|
author | Fiksinski, Ania M. Hoftman, Gil D. Vorstman, Jacob A. S. Bearden, Carrie E. |
author_facet | Fiksinski, Ania M. Hoftman, Gil D. Vorstman, Jacob A. S. Bearden, Carrie E. |
author_sort | Fiksinski, Ania M. |
collection | PubMed |
description | Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype–phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics. |
format | Online Article Text |
id | pubmed-9812786 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-98127862023-01-06 A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome Fiksinski, Ania M. Hoftman, Gil D. Vorstman, Jacob A. S. Bearden, Carrie E. Mol Psychiatry Expert Review Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype–phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics. Nature Publishing Group UK 2022-10-03 2023 /pmc/articles/PMC9812786/ /pubmed/36192458 http://dx.doi.org/10.1038/s41380-022-01783-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Expert Review Fiksinski, Ania M. Hoftman, Gil D. Vorstman, Jacob A. S. Bearden, Carrie E. A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome |
title | A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome |
title_full | A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome |
title_fullStr | A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome |
title_full_unstemmed | A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome |
title_short | A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome |
title_sort | genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome |
topic | Expert Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9812786/ https://www.ncbi.nlm.nih.gov/pubmed/36192458 http://dx.doi.org/10.1038/s41380-022-01783-5 |
work_keys_str_mv | AT fiksinskianiam ageneticsfirstapproachtounderstandingautismandschizophreniaspectrumdisordersthe22q112deletionsyndrome AT hoftmangild ageneticsfirstapproachtounderstandingautismandschizophreniaspectrumdisordersthe22q112deletionsyndrome AT vorstmanjacobas ageneticsfirstapproachtounderstandingautismandschizophreniaspectrumdisordersthe22q112deletionsyndrome AT beardencarriee ageneticsfirstapproachtounderstandingautismandschizophreniaspectrumdisordersthe22q112deletionsyndrome AT fiksinskianiam geneticsfirstapproachtounderstandingautismandschizophreniaspectrumdisordersthe22q112deletionsyndrome AT hoftmangild geneticsfirstapproachtounderstandingautismandschizophreniaspectrumdisordersthe22q112deletionsyndrome AT vorstmanjacobas geneticsfirstapproachtounderstandingautismandschizophreniaspectrumdisordersthe22q112deletionsyndrome AT beardencarriee geneticsfirstapproachtounderstandingautismandschizophreniaspectrumdisordersthe22q112deletionsyndrome |