Within-family influences on dimensional neurobehavioral traits in a high-risk genetic model

Fiksinski, Ania; Heung, Tracy; Corral, Maria; Breetvelt, Elemi J.; Costain, Gregory; Marshall, Christian R.; Kahn, René S.; Vorstman, Jacob; Bassett, Anne S.

doi:10.1017/s0033291720005279

Cited by 11 publications

(9 citation statements)

References 43 publications

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“…Current empirical evidence supports this mechanism for the phenotypes of IQ and schizophrenia, but it is not yet known if this pattern generalizes to other brain-related phenotypes. A recent study of cognitive, social, and motor phenotypes in individuals with a de novo 22q11.2 deletion and their unaffected parents found a significant association between parental and offspring cognitive functioning, consistent with the polygenic score findings [133].…”

Section: Variable Penetrance and Expressivitysupporting

confidence: 70%

A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome

et al. 2022

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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.

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Section: Variable Penetrance and Expressivitysupporting

confidence: 70%

A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome

et al. 2022

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“…This is in line with studies showing that IQ variance within groups of 16p11.2 and 22q11.2 deletion carriers is similar to that in the general population, although the mean IQ is significantly lower. Therefore, variance in CNV groups is thought to be related to additive effects of genetic (and non-genetic) factors that are captured by parental IQ and common variants (11,23,(28)(29)(30) (Figure 2).…”

Section: Phenotypic Variabilitymentioning

confidence: 99%

Genes To Mental Health (G2MH): A Framework to Map the Combined Effects of Rare and Common Variants on Dimensions of Cognition and Psychopathology

Jacquemont¹,

Huguet²,

Klein³

et al. 2022

AJP

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Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders (NPDs). In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the effects on dimensional traits remain unclear for many RGDs. The nature and specificity of RGD effects on cognitive and behavioral traits is an area of intense investigation: RGDs are frequently associated with more than one psychiatric condition and those studied to date affect, to varying degrees, a broad range of developmental and cognitive functions. Although many RGDs have large effects, phenotypic expression is typically influenced by additional genomic and environmental factors. There is emerging evidence that using polygenic risk scores in individuals with RGDs offers opportunities to refine prediction, thus allowing for the identification of those at greatest risk of psychiatric illness. However, translation into the clinic is hindered by roadblocks, which include limited genetic testing in clinical psychiatry, and the lack of guidelines for following individuals with RGDs, who are at high risk of developing psychiatric symptoms. The Genes 2 Mental Health Network (G2MH) is a newly funded NIMH initiative that will collect, share and analyze large scale datasets combining genomics and dimensional measures of psychopathology spanning diverse populations and geography. We present here the most recent understanding of the effects of RGDs on dimensional behavioral traits and risk for psychiatric conditions. We discuss strategies that will be pursued within the G2MH network, and how expected results can be translated into clinical practice to improve patient outcomes.Plain Language summary 60 words. Genomic methods are widely used in psychiatric research and are recommended in clinical practice to identify rare genomic variants in patients with neurodevelopmental disorders. However, we still know very little about these variants. The mission of G2MH is to collect and harmonize clinical and genomic data on large groups of individuals who carry such rare variants to understand how they affect cognition and behavior and increase the risk for psychiatric conditions.

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“…This will include considerations such as expected assortative mating, the degree of similarity in parental FSIQ, and potentially different effects of intra-uterine environment between maternally inherited and paternally inherited 22q11.2 deletions. A high correlation in FSIQ between parents, and between parents and their offspring, is expected from both studies of the general population and of individuals with de novo 22q11.2 deletions [ 18 ]. Consistent with these expected parental findings for de novo 22q11.2 deletions, there are preliminary data from a previous study of children with inherited 22q11.2 deletions indicating some concordance in educational attainment of both parents, i.e., one with and one without a 22q11.2 deletion, though the affected parent was not indicated [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…For example, the 22q11.2 deletion extent may be important, given a slightly but significantly higher FSIQ reported in individuals with nested LCR22A-LCR22B deletions [ 13 ]. It is also possible that there may be differences in effect between verbal and performance IQ that were not examined in the current study [ 10 , 13 , 18 , 24 ]. There are also important differences in cohorts related to differing ascertainment and other methodological issues, e.g., pediatric vs. adult aged cohorts and general genetics vs. subspecialty clinics.…”

Section: Discussionmentioning

confidence: 99%

“…Demographic and clinical features such as sex, CHD, hypocalcemia, and attention deficit disorder have shown no association with cognitive outcomes [ 10 , 13 , 14 , 15 , 16 ]. However, in addition to the major effect of the chromosome 22q11.2 deletion itself, there is now evidence for age, major psychotic illness, and background (e.g., mid-parental FSIQ), playing a role in FSIQ outcomes, as they do in the general population [ 17 , 18 , 19 , 20 ]. There are limited data, however, on the challenging-to-study areas of inheritance and parental origin of the chromosome 22q11.2 deletion; e.g., no study has reported FSIQ data for more than 11 inherited deletions [ 10 , 11 , 17 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Influence of Parent-of-Origin on Intellectual Outcomes in the Chromosome 22q11.2 Deletion Syndrome

McGinn

Crowley

Heung

et al. 2022

Genes

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Learning and intellectual disabilities are hallmark features of 22q11.2 deletion syndrome. Data are limited, however, regarding influences on full-scale IQ (FSIQ). Here, we investigated possible 22q11.2 deletion parent-of-origin effects. In 535 individuals, we compared FSIQ (≥50), 481 with de novo and 54 with inherited 22q11.2 deletions. In the subsets with data available, we examined parent-of-origin effects on FSIQ. We used linear regression models to account for covariates. Median FSIQ was significantly higher in de novo vs. inherited deletions (77; range 50–116 vs. 67; range 50–96, p < 0.0001). Results remained significant using a regression model accounting for age at IQ testing, sex and cohort site. No significant parent-of-origin differences in FSIQ were observed for de novo deletions (n = 81, 63.0% maternal; p = 0.6882). However, median FSIQ was significantly lower in maternally than in paternally inherited familial deletions (65, range 50–86 vs. 71.5, range 58–96, respectively, p = 0.0350), with the regression model indicating an ~8 point decrement in FSIQ for this variable (p = 0.0061). FSIQ is higher on average in de novo than in inherited 22q11.2 deletions, regardless of parental origin. However, parent-of-origin appears relevant in inherited deletions. The results have potential clinical implications with further research needed to delineate possible actionable mechanisms.

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Within-family influences on dimensional neurobehavioral traits in a high-risk genetic model

Cited by 11 publications

References 43 publications

A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome

A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome

Genes To Mental Health (G2MH): A Framework to Map the Combined Effects of Rare and Common Variants on Dimensions of Cognition and Psychopathology

Influence of Parent-of-Origin on Intellectual Outcomes in the Chromosome 22q11.2 Deletion Syndrome

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