Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk.

BACKGROUND AND AIMS: RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases. METHODS: RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank. RESULTS: In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60). CONCLUSIONS: PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.

NuA4 and SAGA acetyltransferase complexes cooperate for repair of DNA breaks by homologous recombination.

Chromatin modifying complexes play important yet not fully defined roles in DNA repair processes. The essential NuA4 histone acetyltransferase (HAT) complex is recruited to double-strand break (DSB) sites and spreads along with DNA end resection. As predicted, NuA4 acetylates surrounding nucleosomes upon DSB induction and defects in its activity correlate with altered DNA end resection and Rad51 recombinase recruitment. Importantly, we show that NuA4 is also recruited to the donor sequence during recombination along with increased H4 acetylation, indicating a direct role during strand invasion/D-loop formation after resection. We found that NuA4 cooperates locally with another HAT, the SAGA complex, during DSB repair as their combined action is essential for DNA end resection to occur. This cooperation of NuA4 and SAGA is required for recruitment of ATP-dependent chromatin remodelers, targeted acetylation of repair factors and homologous recombination. Our work reveals a multifaceted and conserved cooperation mechanism between acetyltransferase complexes to allow repair of DNA breaks by homologous recombination.

Antagonistic relationship of NuA4 with the non-homologous end-joining machinery at DNA damage sites.

The NuA4 histone acetyltransferase complex, apart from its known role in gene regulation, has also been directly implicated in the repair of DNA double-strand breaks (DSBs), favoring homologous recombination (HR) in S/G2 during the cell cycle. Here, we investigate the antagonistic relationship of NuA4 with non-homologous end joining (NHEJ) factors. We show that budding yeast Rad9, the 53BP1 ortholog, can inhibit NuA4 acetyltransferase activity when bound to chromatin in vitro. While we previously reported that NuA4 is recruited at DSBs during the S/G2 phase, we can also detect its recruitment in G1 when genes for Rad9 and NHEJ factors Yku80 and Nej1 are mutated. This is accompanied with the binding of single-strand DNA binding protein RPA and Rad52, indicating DNA end resection in G1 as well as recruitment of the HR machinery. This NuA4 recruitment to DSBs in G1 depends on Mre11-Rad50-Xrs2 (MRX) and Lcd1/Ddc2 and is linked to the hyper-resection phenotype of NHEJ mutants. It also implicates NuA4 in the resection-based single-strand annealing (SSA) repair pathway along Rad52. Interestingly, we identified two novel non-histone acetylation targets of NuA4, Nej1 and Yku80. Acetyl-mimicking mutant of Nej1 inhibits repair of DNA breaks by NHEJ, decreases its interaction with other core NHEJ factors such as Yku80 and Lif1 and favors end resection. Altogether, these results establish a strong reciprocal antagonistic regulatory function of NuA4 and NHEJ factors in repair pathway choice and suggests a role of NuA4 in alternative repair mechanisms in situations where some DNA-end resection can occur in G1.

Sensory processing dysregulations as reliable translational biomarkers in SYNGAP1 haploinsufficiency.

Amongst the numerous genes associated with intellectual disability, SYNGAP1 stands out for its frequency and penetrance of loss-of-function variants found in patients, as well as the wide range of co-morbid disorders associated with its mutation. Most studies exploring the pathophysiological alterations caused by Syngap1 haploinsufficiency in mouse models have focused on cognitive problems and epilepsy; however, whether and to what extent sensory perception and processing are altered by Syngap1 haploinsufficiency is less clear. By performing EEG recordings in awake mice, we identified specific alterations in multiple aspects of auditory and visual processing, including increased baseline gamma oscillation power, increased theta/gamma phase amplitude coupling following stimulus presentation and abnormal neural entrainment in response to different sensory modality-specific frequencies. We also report lack of habituation to repetitive auditory stimuli and abnormal deviant sound detection. Interestingly, we found that most of these alterations are present in human patients as well, thus making them strong candidates as translational biomarkers of sensory-processing alterations associated with SYNGAP1/Syngap1 haploinsufficiency.

Developmental course of the repetition effect and change detection responses from infancy through childhood: a longitudinal study.

Neuronal repetition effect (repetition suppression and repetition enhancement) and change detection responses are fundamental brain responses that have implications in learning and cognitive development in infants and children. Studies have shown altered neuronal repetition and change detection responses in various clinical populations. However, the developmental course of these neuronal responses from infancy through childhood is still unknown. Using an electroencephalography oddball task, we investigate the developmental peculiarities of repetition effect and change detection responses in 43 children that we followed longitudinally from 3 months to 4 years of age. Analyses were conducted on theta (3-5 Hz), alpha (5-10 Hz), and beta (10-30 Hz) time-frequency windows. Results indicated that in the theta time-frequency window, in frontocentral and frontal regions of the brain, repetition and change detection responses followed a U-shaped pattern from 3 months to 4 years of age. Moreover, the change detection response was stronger in young infants compared to older children in frontocentral regions, regardless of the time-frequency window. Our findings add to the evidence of top-down modulation of perceptual systems in infants and children.

Infant repetition effects and change detection: Are they related to adaptive skills?

Repetition effects and change detection response have been proposed as neuro-electrophysiological correlates of fundamental learning processes. As such, they could be a good predictor of brain maturation and cognitive development. We recorded high density EEG in 71 healthy infants (32 females) aged between 3 and 9 months, while they listened to vowel sequences (standard /a/a/a/i/ [80%] and deviant /a/a/a/a/ [20%]). Adaptive skills, a surrogate of cognitive development, were measured via the parent form of the Adaptive Behavior Assessment System Second Edition (ABAS-II). Cortical auditory-evoked potentials (CAEPs) analyses, time-frequency analyses and a statistical approach using linear mixed models (LMMs) and linear regression models were performed. Age and adaptive skills were tested as predictors. Age modulation of repetition effects and change detection response was observed in theta (3-5 Hz), alpha (5-10 Hz) and high gamma (80-90 Hz) oscillations and in all CAEPs. Moreover, adaptive skills modulation of repetition effects was evidenced in theta (3-5 Hz), high gamma oscillations (80-90 Hz), N250/P350 peak-to-peak amplitude and P350 latency. Finally, adaptive skills modulation of change detection response was observed in the N250/P350 peak-to-peak amplitude. Our results confirm that repetition effects and change detection response evolve with age. Moreover, our results suggest that repetition effects and change detection response vary according to adaptive skills displayed by infants during the first year of life, demonstrating their predictive value for neurodevelopment.

Phospho-dependent recruitment of the yeast NuA4 acetyltransferase complex by MRX at DNA breaks regulates RPA dynamics during resection.

The KAT5 (Tip60/Esa1) histone acetyltransferase is part of NuA4, a large multifunctional complex highly conserved from yeast to mammals that targets lysines on H4 and H2A (X/Z) tails for acetylation. It is essential for cell viability, being a key regulator of gene expression, cell proliferation, and stem cell renewal and an important factor for genome stability. The NuA4 complex is directly recruited near DNA double-strand breaks (DSBs) to facilitate repair, in part through local chromatin modification and interplay with 53BP1 during the DNA damage response. While NuA4 is detected early after appearance of the lesion, its precise mechanism of recruitment remains to be defined. Here, we report a stepwise recruitment of yeast NuA4 to DSBs first by a DNA damage-induced phosphorylation-dependent interaction with the Xrs2 subunit of the Mre11-Rad50-Xrs2 (MRX) complex bound to DNA ends. This is followed by a DNA resection-dependent spreading of NuA4 on each side of the break along with the ssDNA-binding replication protein A (RPA). Finally, we show that NuA4 can acetylate RPA and regulate the dynamics of its binding to DNA, hence targeting locally both histone and nonhistone proteins for lysine acetylation to coordinate repair.

Premaxillary Setback With Posterior Vomerine Ostectomy: Outcomes of Single-Stage Repair of Complete Bilateral Cleft Lip With a Severely Protruding Premaxilla.

OBJECTIVE: Evaluating the safety and outcomes of premaxillary setback with posterior vomerine ostectomy in single-stage repair of complete bilateral cleft lip (CBCL) with severe premaxillary protrusion. DESIGN: Retrospective case series. SETTING: Multiple outreach surgical sites. PATIENTS/PARTICIPANTS: From 2012 to 2016, 41 patients with CBCL and severe premaxillary protrusion underwent posterior vomerine premaxillary setback (PVPS) by a single surgeon in Brazil, Ecuador, and Peru. Patients 4 months to 18 years old undergoing primary or revision CBCL surgery were eligible for inclusion in the study. Patients with diagnosed syndromes were excluded. INTERVENTIONS: Posterior vomerine premaxillary setback. MAIN OUTCOME MEASURES: Postoperative complications and postoperative aesthetic outcomes. RESULTS: The mean age at surgery was 3.7 ± 3.8 years, with an average follow-up time of 17.0 ± 13.9 months. Patients underwent their procedures in Brazil (71%), Ecuador (22%), and Peru (7%). The majority of patients were aged 2 years or less (56%), were males (54%), had undergone prior surgery (56%), and had not undergone preoperative surgical orthopedics (95%). None of the patients developed major complications. All patients were able to undergo PVPS with concomitant required procedures and had good aesthetic outcomes. CONCLUSIONS: Few reports have evaluated single-stage CBCL repair or revision with severe premaxillary protrusion using PVPS. Our study shows that this technique is safe and results in good aesthetic outcomes. Further follow-up with anthropometric patient data is needed to evaluate long-term postoperative outcomes.

Eaf5/7/3 form a functionally independent NuA4 submodule linked to RNA polymerase II-coupled nucleosome recycling.

The NuA4 histone acetyltransferase complex is required for gene regulation, cell cycle progression, and DNA repair. Dissection of the 13-subunit complex reveals that the Eaf7 subunit bridges Eaf5 with Eaf3, a H3K36me3-binding chromodomain protein, and this Eaf5/7/3 trimer is anchored to NuA4 through Eaf5. This trimeric subcomplex represents a functional module, and a large portion exists in a native form outside the NuA4 complex. Gene-specific and genome-wide location analyses indicate that Eaf5/7/3 correlates with transcription activity and is enriched over the coding region. In agreement with a role in transcription elongation, the Eaf5/7/3 trimer interacts with phosphorylated RNA polymerase II and helps its progression. Loss of Eaf5/7/3 partially suppresses intragenic cryptic transcription arising in set2 mutants, supporting a role in nucleosome destabilization. On the other hand, loss of the trimer leads to an increase of replication-independent histone exchange over the coding region of transcribed genes. Taken together, these results lead to a model where Eaf5/7/3 associates with elongating polymerase to promote the disruption of nucleosomes in its path, but also their refolding in its wake.

HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail.

The HBO1 HAT protein is the major source of histone H4 acetylation in vivo and has been shown to play critical roles in gene regulation and DNA replication. A distinctive characteristic of HBO1 HAT complexes is the presence of three PHD finger domains in two different subunits: tumor suppressor proteins ING4/5 and JADE1/2/3. Biochemical and functional analyses indicate that these domains interact with histone H3 N-terminal tail region, but with a different specificity toward its methylation status. Their combinatorial action is essential in regulating chromatin binding and substrate specificity of HBO1 complexes, as well as cell growth. Importantly, localization analyses on the human genome indicate that HBO1 complexes are enriched throughout the coding regions of genes, supporting a role in transcription elongation. These results underline the importance and versatility of PHD finger domains in regulating chromatin association and histone modification crosstalk within a single protein complex.

Soft and Firm Alloplastic Implants in Rhinoplasty: Why, When and How to Use Them: A Review of 311 Cases.

BACKGROUND: Modern rhinoplasty is not just a reduction procedure. An optimal nasal esthetic result occasionally requires augmenting the nasal tip, the dorsum or the lateral wall with autografts or alloplasts. A large number of nasal implant types have been reported in the medical literature. OBJECTIVE: The goal of this article is to demystify the role and indications of nasal implants in rhinoplasty. As well, it offers both the novice and experienced nasal surgeon a basic, simplified and organized approach to the use of soft and firm nasal implants in rhinoplasty. METHODS: This article presents the authors experience with 311 rhinoplasties using both soft and firm alloplastic implants. The indications for both types of alloplasts are discussed, the surgical technique detailed and the outcomes analyzed. RESULTS: A total of 311 nasal implant cases were reviewed. This series revealed a low incidence of postoperative infection (5.57% for soft implants and 0.1% for the firm ones). The revision rate was 2.7% for the soft implants group and 7.1% for the firm implants group. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

EEG repetition and change detection responses in infancy predict adaptive functioning in preschool age: a longitudinal study.

Neurodevelopmental disorders (NDDs) are mostly diagnosed around the age of 4-5 years, which is too late considering that the brain is most susceptive to interventions during the first two years of life. Currently, diagnosis of NDDs is based on observed behaviors and symptoms, but identification of objective biomarkers would allow for earlier screening. In this longitudinal study, we investigated the relationship between repetition and change detection responses measured using an EEG oddball task during the first year of life and at two years of age, and cognitive abilities and adaptive functioning during preschool years (4 years old). Identification of early biomarkers is challenging given that there is a lot of variability in developmental courses among young infants. Therefore, the second aim of this study is to assess whether brain growth is a factor of interindividual variability that influences repetition and change detection responses. To obtain variability in brain growth beyond the normative range, infants with macrocephaly were included in our sample. Thus, 43 normocephalic children and 20 macrocephalic children were tested. Cognitive abilities at preschool age were assessed with the WPPSI-IV and adaptive functioning was measured with the ABAS-II. Time-frequency analyses were conducted on the EEG data. Results indicated that repetition and change detection responses in the first year of life predict adaptive functioning at 4 years of age, independently of head circumference. Moreover, our findings suggested that brain growth explains variability in neural responses mostly in the first years of life, so that macrocephalic children did not display repetition suppression responses, while normocephalic children did. This longitudinal study demonstrates that the first year of life is an important period for the early screening of children at risk of developing NDDs.

Time-frequency analyses of repetition suppression and change detection in children with neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF1) are at increased risk of developing cognitive problems, including attention deficits and learning difficulties. Alterations in brain response to repetition and change have been evidenced in other genetic conditions associated with cognitive dysfunctions. Whether the integrity of these fundamental neural responses is compromised in school-aged children with NF1 is still unknown. In this study, we examined the repetition suppression (RS) and change detection responses in children with NF1 (n = 36) and neurotypical controls (n = 41) aged from 4 to 13 years old, using a simple sequence of vowels. We performed time-frequency analyses to compare spectral power and phase synchronization between groups, in the theta, alpha and beta frequency bands. Correlational analyses were performed between the neural responses and the level of intellectual functioning, as well as with behavioral symptoms of comorbid neurodevelopmental disorders measured through parental questionnaires. Children with NF1 showed preserved RS, but increased spectral power in the change detection response. Correlational analyses performed with measures of change detection revealed a negative association between the alpha-band spectral power and symptoms of inattention and hyperactivity. These findings suggest atypical neural response to change in children with NF1. Further studies should be conducted to clarify the interaction with comorbid neurodevelopmental disorders and the possible role of altered inhibitory mechanisms in this enhanced neural response.

Impact of brain overgrowth on sensorial learning processing during the first year of life.

Macrocephaly is present in about 2-5% of the general population. It can be found as an isolated benign trait or as part of a syndromic condition. Brain overgrowth has been associated with neurodevelopmental disorders such as autism during the first year of life, however, evidence remains inconclusive. Furthermore, most of the studies have involved pathological or high-risk populations, but little is known about the effects of brain overgrowth on neurodevelopment in otherwise neurotypical infants. We investigated the impact of brain overgrowth on basic perceptual learning processes (repetition effects and change detection response) during the first year of life. We recorded high density electroencephalograms (EEG) in 116 full-term healthy infants aged between 3 and 11 months, 35 macrocephalic (14 girls) and 81 normocephalic (39 girls) classified according to the WHO head circumference norms. We used an adapted oddball paradigm, time-frequency analyses, and auditory event-related brain potentials (ERPs) to investigate differences between groups. We show that brain overgrowth has a significant impact on repetition effects and change detection response in the 10-20 Hz frequency band, and in N450 latency, suggesting that these correlates of sensorial learning processes are sensitive to brain overgrowth during the first year of life.

Corrigendum: EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome.

[This corrects the article DOI: 10.3389/fpsyt.2021.716707.].

DNA Damage-Induced Phosphorylation of Histone H2A at Serine 15 Is Linked to DNA End Resection.

The repair of DNA double-strand breaks (DSBs) occurs in chromatin, and several histone posttranslational modifications have been implicated in the process. Modifications of the histone H2A N-terminal tail have also been linked to DNA damage response, through acetylation or ubiquitination of lysine residues that regulate repair pathway choice. Here, we characterize a new DNA damage-induced phosphorylation on chromatin, at serine 15 of H2A in yeast. We show that this SQ motif functions independently of the classical S129 C-terminal site (γ-H2A) and that mutant-mimicking constitutive phosphorylation increases cell sensitivity to DNA damage. H2AS129ph is induced by Tel1ATM and Mec1ATR, and the loss of Lcd1ATRIP or Mec1 signaling decreases γ-H2A spreading distal to the DSB. In contrast, H2AS15ph is completely dependent on Lcd1ATRIP, indicating that this modification only happens when end resection is engaged. This is supported by an increase in replication protein A (RPA) and a decrease in DNA signal near the DSB in H2A-S15E phosphomimic mutants, indicating higher resection. In mammals, this serine is replaced by a lysine (H2AK15) which undergoes an acetyl-monoubiquityl switch to regulate binding of 53BP1 and resection. This regulation seems functionally conserved with budding yeast H2AS15 and 53BP1-homolog Rad9, using different posttranslational modifications between organisms but achieving the same function.

Differential auditory brain response abnormalities in two intellectual disability conditions: SYNGAP1 mutations and Down syndrome.

OBJECTIVE: Altered sensory processing is common in intellectual disability (ID). Here, we study electroencephalographic responses to auditory stimulation in human subjects presenting a rare condition (mutations in SYNGAP1) which causes ID, epilepsy and autism. METHODS: Auditory evoked potentials, time-frequency and inter-trial coherence analyses were used to compare subjects with SYNGAP1 mutations with Down syndrome (DS) and neurotypical (NT) participants (N = 61 ranging from three to 19 years of age). RESULTS: Altered synchronization in the brain responses to sound were found in both ID groups. The SYNGAP1 mutations group showed less phase-locking in early time windows and lower frequency bands compared to NT, and in later time windows compared to NT and DS. Time-frequency analysis showed more power in beta-gamma in the SYNGAP1 group compared to NT participants. CONCLUSIONS: This study indicated reduced synchronization as well as more high frequencies power in SYNGAP1 mutations, while maintained synchronization was found in the DS group. These results might reflect dysfunctional sensory information processing caused by excitation/inhibition imbalance, or an imperfect compensatory mechanism in SYNGAP1 mutations individuals. SIGNIFICANCE: Our study is the first to reveal brain response abnormalities in auditory sensory processing in SYNGAP1 mutations individuals, that are distinct from DS, another ID condition.

Distinct patterns of repetition suppression in Fragile X syndrome, down syndrome, tuberous sclerosis complex and mutations in SYNGAP1.

Sensory processing is the gateway to information processing and more complex processes such as learning. Alterations in sensory processing is a common phenotype of many genetic syndromes associated with intellectual disability (ID). It is currently unknown whether sensory processing alterations converge or diverge on brain responses between syndromes. Here, we compare for the first time four genetic conditions with ID using the same basic sensory learning paradigm. One hundred and five participants, aged between 3 and 30 years old, composing four clinical ID groups and one control group, were recruited: Fragile X syndrome (FXS; n = 14), tuberous sclerosis complex (TSC; n = 9), Down syndrome (DS; n = 19), SYNGAP1 mutations (n = 8) and Neurotypical controls (NT; n = 55)). All groups included female and male participants. Brain responses were recorded using electroencephalography (EEG) during an audio-visual task that involved three repetitions of the pronunciation of the phoneme /a/. Event Related Potentials (ERP) were used to: 1) compare peak-to-peak amplitudes between groups, 2) evaluate the presence of repetition suppression within each group and 3) compare the relative repetition suppression between groups. Our results revealed larger overall amplitudes in FXS. A repetition suppression (RS) pattern was found in the NT group, FXS and DS, suggesting spared repetition suppression in a multimodal task in these two ID syndromes. Interestingly, FXS presented a stronger RS on one peak-to-peak value in comparison with the NT. The results of our study reveal the distinctiveness of ERP and RS brain responses in ID syndromes. Further studies should be conducted to understand the molecular mechanisms involved in these patterns of responses.

EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome.

Introduction: Fragile X syndrome (FXS) is a genetic disorder caused by a mutation of the fragile X mental retardation 1 gene (FMR1). FXS is associated with neurophysiological abnormalities, including cortical hyperexcitability. Alterations in electroencephalogram (EEG) resting-state power spectral density (PSD) are well-defined in FXS and were found to be linked to neurodevelopmental delays. Whether non-linear dynamics of the brain signal are also altered remains to be studied. Methods: In this study, resting-state EEG power, including alpha peak frequency (APF) and theta/beta ratio (TBR), as well as signal complexity using multi-scale entropy (MSE) were compared between 26 FXS participants (ages 5-28 years), and 7 neurotypical (NT) controls with a similar age distribution. Subsequently a replication study was carried out, comparing our cohort to 19 FXS participants independently recorded at a different site. Results: PSD results confirmed the increased gamma, decreased alpha power and APF in FXS participants compared to NT controls. No alterations in TBR were found. Importantly, results revealed reduced signal complexity in FXS participants, specifically in higher scales, suggesting that altered signal complexity is sensitive to brain alterations in this population. The replication study mostly confirmed these results and suggested critical points of stagnation in the neurodevelopmental curve of FXS. Conclusion: Signal complexity is a powerful feature that can be added to the electrophysiological biomarkers of brain maturation in FXS.

Effects of eight neuropsychiatric copy number variants on human brain structure.

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen's d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.