TY - JOUR
T1 - A genetics-first approach to understanding autism and schizophrenia spectrum disorders
T2 - the 22q11.2 deletion syndrome
AU - Fiksinski, Ania M
AU - Hoftman, Gil D
AU - Vorstman, Jacob A S
AU - Bearden, Carrie E
N1 - Funding Information:
This work was partially supported by NIMH U01MH119736 (CEB), NIMH R01MH085953 (CEB), UCLA Friends of the Semel Institute Research Scholar Award (GDH), Karen Seykora NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (GDH), Harvey L. and Maud C. Sorensen Foundation Fellowship (GDH), NIH National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881 (GDH), The SickKids Psychiatry Associates Chair in Developmental Psychopathology and NIMH U01MH119741-01 (JASV), NIMH 5U01MH119740-03 (AMF, PI name T. van Amelsvoort), Grant of patient support group ‘Stichting Steun 22Q11’ (AMF, PI name M. Houben).
Publisher Copyright:
© 2022, The Author(s).
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
U2 - 10.1038/s41380-022-01783-5
DO - 10.1038/s41380-022-01783-5
M3 - (Systematic) Review article
C2 - 36192458
SN - 1359-4184
VL - 28
SP - 341
EP - 353
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 1
ER -