Subcortical Brain Alterations in Carriers of Genomic Copy Number Variants

American Journal of Psychiatry, Год журнала: 2023, Номер 180(9), С. 685 - 698

Опубликована: Июль 12, 2023

Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs), including autism (ASD) schizophrenia. Little is known about how different CNVs conferring the same condition may affect subcortical brain structures these alterations relate to level of disease conferred by CNVs. To fill this gap, authors investigated gross volume, vertex-level thickness, surface maps in 11 six NPDs.

Язык: Английский

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An integrated clinical approach to children at genetic risk for neurodevelopmental and psychiatric conditions: interdisciplinary collaboration and research infrastructure

Journal of Neurodevelopmental Disorders, Год журнала: 2024, Номер 16(1)

Опубликована: Июль 5, 2024

Abstract Background A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a diagnosis often precedes the emergence diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment Genetically Susceptible Youth), novel interdisciplinary ‘genetic-diagnosis-first’ clinic integrating psychiatric, psychological and expertise, report our first observations feedback from families referring clinicians. Methods We retrieved data on referral sources indications, NPD diagnoses recommendations seen at between 2018 2022. Through survey, obtained twenty eleven Results 159 (mean age 10.2 years, 57.2% males) completed an (psychiatry, psychology, counselling) assessment during period. Of these, 69.8% had microdeletion or microduplication, 21.5% sequence-level variant, 4.4% chromosomal disorder, variant unknown significance emerging evidence pathogenicity. One four did not have prior diagnosis, to was motivated by their vulnerability alone. Following assessment, 76.7% received least one new most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) specific learning (16.4%) disorder. Both clinicians responding survey expressed satisfaction, but also highlighted some areas potential improvement. Conclusions addresses unmet clinical need that confer increased provides crucial platform research area. can serve as model clinics child psychiatry, psychology genetics, addressing both needs population.

Язык: Английский

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Convergence and Divergence of Rare Genetic Disorders on Brain Phenotypes

JAMA Psychiatry, Год журнала: 2022, Номер 79(8), С. 818 - 818

Опубликована: Июнь 29, 2022

Importance

Rare genetic disorders modulating gene expression—as exemplified by dosage (GDDs)—represent a collectively common set of high-risk factors for neuropsychiatric illness. Research on GDDs is rapidly expanding because these variants have high effect sizes and known basis. Moreover, the prevalence recurrent (encompassing aneuploidies certain copy number variations) enables genetic-first phenotypic characterization same GDD across multiple individuals, thereby offering unique window into influences human brain behavior. However, rapid growth research has unveiled perplexing convergences divergences genomic loci; while profiles may be specifically associated with variant, individual behavioral neuroimaging traits appear to nonspecifically influenced most GDDs.

Observations

This complexity addressed (1) providing an accessible survey genotype-phenotype mappings different GDDs, focusing psychopathology, cognition, anatomy, (2) detailing both methodological mechanistic sources observed divergences. effort yields recommendations future comparative as well new testable hypotheses regarding aspects early patterning that might govern complex mapping risk onto variation in disorders.

Conclusions Relevance

A roadmap provided boost accurate measurement interrogation convergence divergence Pursuing questions posed could substantially improve our taxonomical, neurobiological, translational understanding

Язык: Английский

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DRAGON-Data: a platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts

BJPsych Open, Год журнала: 2023, Номер 9(2)

Опубликована: Фев. 8, 2023

Background Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic environmental risk factors are shared across disorders. However, the relationship between liability is still poorly understood. Aims Well-characterised, cross-disorder samples needed to investigate this matter, but few currently exist. Our aim develop procedures purposely curate aggregate genotypic phenotypic data research. Method As part Cardiff MRC Mental Health Data Pathfinder initiative, we curated harmonised information from 15 studies create new repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults children with neurodevelopmental or affected probands within collected families individuals who carry known copy number variant. Results We processed available phenotype derive core variables that can be reliably analysed groups. In addition, all data-sets genotype undergone rigorous quality control, imputation, variant calling polygenic score generation. Conclusions combines non-genetic information, as resource for research traditional diagnostic categories. Algorithms pipelines used harmonisation publicly scientific community, an appropriate data-sharing protocol will developed ongoing projects (DATAMIND) partnership Research UK.

Язык: Английский

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Sleep disturbance as a transdiagnostic marker of psychiatric risk in children with neurodevelopmental risk genetic conditions

Translational Psychiatry, Год журнала: 2023, Номер 13(1)

Опубликована: Янв. 11, 2023

Abstract Children with rare neurodevelopmental genetic conditions (ND-GCs) are at high risk for a range of neuropsychiatric conditions. Sleep symptomatology may represent transdiagnostic indicator within this patient group. Here we present data from 629 children ND-GCs, recruited via the United Kingdom’s National Health Service medical clinics. Sibling controls (183) were also invited to take part. Detailed assessments conducted characterise sleep phenotype ND-GCs in comparison controls. Latent class analysis was derive subgroups an ND-GC based on symptomatology. Assessment cognition and psychopathology allowed investigation whether phenotypic subgroup associated outcomes. We found that ND-GC, when compared control siblings, elevated insomnia (ND-GC = 41% vs Controls 17%, p < 0.001) experiencing least one symptom 66% 39%, 0.001). On average, have early onset (2.8 years) impact across multiple contexts. linked psychiatric outcomes (OR ranging 2.0 21.5 depending condition). Our findings demonstrate vulnerability exhibit rates disruption has wide-ranging impacts psychosocial function, indexes those greater risk. Insomnia childhood, highlighting potential intervention strategies informed by profile.

Язык: Английский

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Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe – A multi-professional survey study

European Journal of Medical Genetics, Год журнала: 2023, Номер 66(8), С. 104805 - 104805

Опубликована: Июль 3, 2023

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is lack knowledge guidelines for testing (PsychGT) counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status PsychGT PsychGC across 35 participating countries. Here, we present results pan-European online survey in which gathered opinions, knowledge, practices self-selected sample professionals involved/interested field. We received answers from 181 respondents. three main occupational categories were counselor (21.0%), geneticist (24.9%), researcher (25.4%). Of all respondents, 106 provide GC any disorder or NDD, corresponding 58.6% whole group ranging 43.2% Central Eastern Europe 66.1% Western Europe. Overall, 65.2% respondents reported that offered individuals with 26.5% indicated same Only 22.1% they have PsychGT. Pharmacogenetic actionable by 15%. Interestingly, when tests fully covered national health insurance, more provided NDD but not those Our qualitative analyses responses highlight on utilizing using education training as obstacles implementation. Indeed, existence courses confirmed only 11.6% question relevance up-to-date genetics everyday related practice highly relevant. evidence already use countries, education. Harmonization development counseling, testing, would improve equality access quality care within

Язык: Английский

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Integrative genetic analysis: cornerstone of precision psychiatry

Molecular Psychiatry, Год журнала: 2024, Номер unknown

Опубликована: Авг. 30, 2024

Язык: Английский

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Using rare genetic mutations to revisit structural brain asymmetry

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 26, 2024

Abstract Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection facial cues. Yet, genetic investigations into asymmetry have mostly relied on common variants, which typically exert small effects brain-related phenotypes. Here, we leverage rare genomic deletions duplications to study how alterations reverberate in human behavior. We designed pattern-learning approach dissect impact eight high-effect-size copy number variations (CNVs) multi-site cohort 552 CNV carriers 290 non-carriers. Isolated multivariate patterns spotlighted regions thought subserve lateralized functions, including hearing, well visual, face word recognition. Planum temporale emerged especially susceptible specific gene sets. Targeted analysis variants through genome-wide association (GWAS) consolidated partly diverging influences versus planum structure. In conclusion, our gene-brain-behavior data fusion highlights consequences genetically controlled lateralization uniquely capacities.

Язык: Английский

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Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications

Molecular Psychiatry, Год журнала: 2024, Номер unknown

Опубликована: Июль 24, 2024

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions duplications associated neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying computerized assessment, Penn Computerized Neurocognitive Battery (CNB), administered in multi-site study on rare genomic disorders: deletions (n = 492); 106); deletion 117); 46). Domains examined include executive functions, episodic memory, complex cognition, social psychomotor speed. Accuracy speed each domain were included as dependent mixed-model repeated analysis. Locus (22q11.2, 16p11.2) Copy (deletion/duplication) grouping factors Measure (accuracy, speed) factors, Sex Site covariates. also correlation IQ. found significant × Domain interaction (p 0.0004). greater performance accuracy deficits than duplications, while specific deletions. Duplications both reduced Performance profiles differed among particularly poor memory of group duplication had greatest cognition. Average CNB was moderately correlated Full Scale Deletions have differential effects neurocognition indicating locus specificity profiles. These profile differences can help inform mechanistic substrates heterogeneity presentation outcome, only be established large-scale consortia assessment. Future could aim link clinical features brain function.

Язык: Английский

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Comparison of autism domains across thirty rare variant genotypes

EBioMedicine, Год журнала: 2025, Номер 112, С. 105521 - 105521

Опубликована: Янв. 31, 2025

A number of Neurodevelopmental risk Copy Number Variants (ND-CNVs) and Single Gene (SGVs) are strongly linked to elevated likelihood autism. However, few studies have examined the impact on autism phenotypes across a wide range rare variant genotypes. This study compared Social Communication Questionnaire (SCQ) scores (total subdomains: social, communication, repetitive behaviour) in 1314 young people with one thirty genotypes (15 ND-CNVs; n = 1005, 9.2 ± 3.5 years 15 SGVs; 309, 8.3 4.0 years). Comparisons were also conducted without known genetic conditions (controls; 460, 10.6 3.4 years) idiopathic (n 480, 8.6 3.2 The prevalence indicative (SCQ ≥ 22) was higher those genotype controls (32% vs 2%; OR 43.1, CI 6.6-282.2, p < 0.001) SGVs ND-CNVs (53% 25%; 4.00, 2.2-7.3, 0.002). varied considerably 30 (range 10-85%). associated greater impairment total, communication behaviour subdomains than ND-CNVs. explained limited variation these (η2 between 11.8 21.4%), indicating more convergence divergence phenotype indicated no differences ND-CNVs, whereas showed less behaviour. all genotypes, individuals showing Despite subdomain-specific patterns, there strong evidence for specific genotype-phenotype associations. suggests that alone may predictive value other factors like polygenic environment likely play role. Further research is needed order understand influences, improve prediction inform counselling interventions. work funded by Tackling Multimorbidity at Scale Strategic Priorities Fund programme (MR/W014416/1) (van den Bree) delivered Medical Research Council National Institute Health partnership Economic collaboration Engineering Physical Sciences Council. NIMH U01 MH119738-01 Bree), IMAGINE (Medical UK: MR/T033045/1; MR/N022572/1; MR/L011166/1) UK Centre Grant (MR/L010305/1) (Owen). SJRAC Foundation Fellowship (MRF-058-0015-F-CHAW). We would acknowledge NIH 1R01MH110701-01A1 (PI Mulle), U01MH119736 (CEB), R21MH116473 R01MH085953 Simons (SFARI Explorer Award CEB).

Язык: Английский

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