Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.

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

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

Analyzing the Quality of Life in Individuals with Fragile X Syndrome in Relation to Sleep and Mental Health.

The purpose of this paper was to examine the physical, emotional, social and school functioning domains of quality of life of individuals with Fragile X Syndrome, in relation to mental health and sleep patterns to gain a better understanding of how these aspects are affected by the disorder. This study included 119 individuals with Fragile X Syndrome who were given different cognitive examinations by a neuropsychologist or by parent-proxy questionnaires. This study focused on the Pediatric Quality of Life Inventory (PedsQoL), the Anxiety, Depression and Mood Scale (ADAMS), the Children's Sleep Habits Questionnaire (CSHQ), but did include other cognitive tests (Vineland Adaptive Behaviour Scales, Nonverbal IQ, Autism Diagnostic Observation Schedule). We identified significant associations between decreases in emotional, social and school domains of PedsQoL and the ADAMS subtests of Generalized Anxiety, Manic/Hyperactivity and Obsessive/Compulsivity, with the subtest of Depressed Mood having associations with lower physical and emotional domains. We also identified a significant impact between CSHQ subtests of Sleep Anxiety, Night Wakings, Daytime Sleepiness, and Parasomnia with the emotional and school domains of PedsQoL. There were associations connecting school functioning with Bedtime Resistance, and additional associations connecting emotional functioning with Sleep Duration and Sleep Onset Delay. Physical functioning was also associated with Sleep Anxiety. Our study shows how mental health and sleep defects impact improper sleep patterns and mental health which leads to decreases in the quality of life for individuals with FXS, and how it is important to screen for these symptoms in order to alleviate issues.

Clinical correlates of diagnostic certainty in children and youths with Autistic Disorder.

BACKGROUND: Clinicians diagnosing autism rely on diagnostic criteria and instruments in combination with an implicit knowledge based on clinical expertise of the specific signs and presentations associated with the condition. This implicit knowledge influences how diagnostic criteria are interpreted, but it cannot be directly observed. Instead, insight into clinicians' understanding of autism can be gained by investigating their diagnostic certainty. Modest correlations between the certainty of an autism diagnosis and symptom load have been previously reported. Here, we investigated the associations of diagnostic certainty with specific items of the ADOS as well as other clinical features including head circumference. METHODS: Phenotypic data from the Simons Simplex Collection was used to investigate clinical correlates of diagnostic certainty in individuals diagnosed with Autistic Disorder (n = 1511, age 4 to 18 years). Participants were stratified by the ADOS module used to evaluate them. We investigated how diagnostic certainty was associated with total ADOS scores, age, and ADOS module. We calculated the odds-ratios of being diagnosed with the highest possible certainty given the presence or absence of different signs during the ADOS evaluation. Associations between diagnostic certainty and other cognitive and clinical variables were also assessed. RESULTS: In each ADOS module, some items showed a larger association with diagnostic certainty than others. Head circumference was significantly higher for individuals with the highest certainty rating across all three ADOS modules. In turn, head circumference was positively correlated with some of the ADOS items that were associated with diagnostic certainty, and was negatively correlated with verbal/nonverbal IQ ratio among those assessed with ADOS module 2. LIMITATIONS: The investigated cohort was heterogeneous, e.g. in terms of age, IQ, language level, and total ADOS score, which could impede the identification of associations that only exist in a subgroup of the population. The variability of the certainty ratings in the sample was low, limiting the power to identify potential associations with other variables. Additionally, the scoring of diagnostic certainty may vary between clinicians. CONCLUSION: Some ADOS items may better capture the signs that are most associated with clinicians' implicit knowledge of Autistic Disorder. If replicated in future studies, new diagnostic instruments with differentiated weighting of signs may be needed to better reflect this, possibly resulting in better specificity in standardized assessments.

Genetic and phenotypic similarity across major psychiatric disorders: a systematic review and quantitative assessment.

There is widespread overlap across major psychiatric disorders, and this is the case at different levels of observations, from genetic variants to brain structures and function and to symptoms. However, it remains unknown to what extent these commonalities at different levels of observation map onto each other. Here, we systematically review and compare the degree of similarity between psychiatric disorders at all available levels of observation. We searched PubMed and EMBASE between January 1, 2009 and September 8, 2022. We included original studies comparing at least four of the following five diagnostic groups: Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Autism Spectrum Disorder, and Attention Deficit Hyperactivity Disorder, with measures of similarities between all disorder pairs. Data extraction and synthesis were performed by two independent researchers, following the PRISMA guidelines. As main outcome measure, we assessed the Pearson correlation measuring the degree of similarity across disorders pairs between studies and biological levels of observation. We identified 2975 studies, of which 28 were eligible for analysis, featuring similarity measures based on single-nucleotide polymorphisms, gene-based analyses, gene expression, structural and functional connectivity neuroimaging measures. The majority of correlations (88.6%) across disorders between studies, within and between levels of observation, were positive. To identify a consensus ranking of similarities between disorders, we performed a principal component analysis. Its first dimension explained 51.4% (95% CI: 43.2, 65.4) of the variance in disorder similarities across studies and levels of observation. Based on levels of genetic correlation, we estimated the probability of another psychiatric diagnosis in first-degree relatives and showed that they were systematically lower than those observed in population studies. Our findings highlight that genetic and brain factors may underlie a large proportion, but not all of the diagnostic overlaps observed in the clinic.

Copy number variants differ in frequency across genetic ancestry groups.

Copy number variants (CNVs) have been implicated in a variety of neuropsychiatric and cognitive phenotypes. We found that deleterious CNVs are less prevalent in non-European ancestry groups than they are in European ancestry groups of both the UK Biobank (UKBB) and a U.S. replication cohort (SPARK). We also identified specific recurrent CNVs that consistently differ in frequency across ancestry groups in both the UKBB and SPARK. These ancestry-related differences in CNV prevalence present in both an unselected community population and a family cohort enriched with individuals diagnosed with autism spectrum disorder (ASD) strongly suggest that genetic ancestry should be considered when probing associations between CNVs and health outcomes.

High-effect gene-coding variants impact cognition, mental well-being, and neighborhood safety substrates in brain morphology.

Our genetic makeup, together with environmental and social influences, shape our brain's development. Yet, the imaging genetics field has struggled to integrate all these modalities to investigate the interplay between genetic blueprint, environment, human health, daily living skills and outcomes. Hence, we interrogated the Adolescent Brain Cognitive Development (ABCD) cohort to outline the effects of rare high-effect genetic variants on brain architecture and corresponding implications on cognitive, behavioral, psychosocial, and socioeconomic traits. Specifically, we designed a holistic pattern-learning algorithm that quantitatively dissects the impacts of copy number variations (CNVs) on brain structure and 962 behavioral variables spanning 20 categories in 7,657 adolescents. Our results reveal associations between genetic alterations, higher-order brain networks, and specific parameters of the family well-being (increased parental and child stress, anxiety and depression) or neighborhood dynamics (decreased safety); effects extending beyond the impairment of cognitive ability or language capacity, dominantly reported in the CNV literature. Our investigation thus spotlights a far-reaching interplay between genetic variation and subjective life quality in adolescents and their families.

Pervasive alterations of intra-axonal volume and network organization in young children with a 16p11.2 deletion.

Reciprocal Copy Number Variants (CNVs) at the 16p11.2 locus confer high risk for autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDDs). Morphometric MRI studies have revealed large and pervasive volumetric alterations in carriers of a 16p11.2 deletion. However, the specific neuroanatomical mechanisms underlying such alterations, as well as their developmental trajectory, are still poorly understood. Here we explored differences in microstructural brain connectivity between 24 children carrying a 16p11.2 deletion and 66 typically developing (TD) children between 2 and 8 years of age. We found a large pervasive increase of intra-axonal volume widespread over a high number of white matter tracts. Such microstructural alterations in 16p11.2 deletion children were already present at an early age, and led to significant changes in the global efficiency and integration of brain networks mainly associated to language, motricity and socio-emotional behavior, although the widespread pattern made it unlikely to represent direct functional correlates. Our results shed light on the neuroanatomical basis of the previously reported increase of white matter volume, and align well with analogous evidence of altered axonal diameter and synaptic function in 16p11.2 mice models. We provide evidence of a prevalent mechanistic deviation from typical maturation of brain structural connectivity associated with a specific biological risk to develop ASD. Future work is warranted to determine how this deviation contributes to the emergence of symptoms observed in young children diagnosed with ASD and other NDDs.

Longitudinal follow-up of metformin treatment in Fragile X Syndrome.

Introduction: Metformin has been used as a targeted treatment to potentially improve cognition and slow the typical IQ decline that occurs during development among individuals with fragile X syndrome (FXS). In this follow-up study, we are following the trajectory of IQ and adaptive behavior changes over 1 to 3 years in individuals with FXS who are clinically treated with metformin in an open label trial. Method: Individuals with FXS ages 6 to 25 years (mean 13.15 ± 5.50) and nonverbal IQ mean 57.69 (±15.46) were treated for 1-3 years (1.88 ± 0.63). They all had a baseline IQ test using the Leiter-III non-verbal cognitive assessment and the Vineland-III adaptive behavior assessment before the start of metformin. Repeat Leiter-III and Vineland-III were completed after at least 1 year of metformin (500-1,000 mg/dose given twice a day). Result: There were no significant changes in non-verbal IQ or in the adaptive behavior measurements at FDR < 0.05. The findings thus far indicate that both IQ and adaptive behavior are stable over time, and we did not see a significant decline in either measure. Conclusion: Overall, the small sample size and short follow-up duration limit the interpretation of the effects of metformin on cognitive development and adaptive functioning. There is individual variability but overall for the group there was no significant decline in IQ or adaptive behavior.

Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability.

Introduction: Rare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer susceptibility for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD susceptibility, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability. Methods: In a cohort of 8,426 subjects with ASD and 169,804 controls with cognitive assessments, we found that rare coding CNVs and PRS-IQ increased ASD risk, even after adjusting for their effects on cognitive ability. Results: Bottom decile PRS-IQ and CNVs both decreased cognitive ability but had opposing effects on ASD risk. Models combining both classes of variants showed that the effects of rare CNVs and PRS-IQ on ASD risk and cognitive ability were largely additive, further suggesting that susceptibility for ASD is conferred independently from its effects on cognitive ability. Despite imparting mostly additive effects on ASD risk, rare CNVs and PRS-IQ showed opposing effects on core and associated features and developmental history among subjects with ASD. Discussion: Our findings suggest that cognitive ability itself may not be the factor driving the underlying liability for ASD conferred by these two classes of genomic variants. In other words, ASD risk and cognitive ability may be two distinct manifestations of CNVs and PRS-IQ. This study also highlights the challenge of understanding how genetic risk for ASD maps onto its dimensional traits.

Using rare genetic mutations to revisit structural brain asymmetry.

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

Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders.

Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.

Neurocognitive Profiles of 22q11.2 and 16p11.2 Deletions and Duplications.

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are among the most common rare genetic disorders associated with significant risk for neuropsychiatric disorders across the lifespan. Microdeletions and duplications in these loci are associated with neurocognitive deficits, yet there are few studies comparing these groups using the same measures. We address this gap in a prospective international collaboration applying the same computerized neurocognitive assessment. The Penn Computerized Neurocognitive Battery (CNB) was administered in a multi-site study on rare genomic disorders: 22q11.2 deletion (n = 397); 22q11.2 duplication (n = 77); 16p11.2 deletion (n = 94); and 16p11.2 duplication (n = 26). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and sensori-motor speed. Accuracy and speed for each neurocognitive domain were included as dependent measures in a mixed-model repeated measures analysis, with locus (22q11.2, 16p11.2) and copy number (deletion/duplication) as grouping factors and neurocognitive domain as a repeated measures factor, with age and sex as covariates. We also examined correlation with IQ and site effects. We found that 22q11.2 deletions were associated with greater deficits in overall performance accuracy than 22q11.2 duplications, while 16p11.2 duplications were associated with greater deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed. Performance profiles differed among the groups with particularly poor performance of 16p11.2 duplication on non-verbal reasoning and social cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. No site effects were observed. Deletions and duplications of 22q11.2 and 16p11.2 have varied effects on neurocognition indicating locus specificity, with performance profiles differing among the groups. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome. Future studies could aim to link performance profiles to clinical features and brain function.