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Preliminary evidence from the Childhood Joint Attention Rating Scale (C-JARS; Mundy et al., 2017) suggests symptoms related to diminished joint attention and the spontaneous sharing of experience with others can be assessed with a parent-report measure in children and adolescents with autism. This study was designed to expand on the previous study by examining the validity of both a Social Symptom (SS) and a Prosocial (PS) scale of the C-JARS in a study of school-aged autistic children (n  = 89) with and without co-occurring intellectual disability (ID), as well as an age matched neurotypical sample (n  = 62). Results indicated that both C-JARS scales were sensitive and specific with respect to identifying the diagnostic status of the children. In addition, the PS scale was sensitive to differences in cognitive abilities (IQ) and sex differences in the autism group. These results are consistent with the hypothesis that joint attention and spontaneous sharing of experience symptoms are not only characteristic of preschool children with autism but may also constitute a developmentally continuous dimension of the social phenotype of autism that can be measured in school-aged children.

BackgroundIndividuals with intellectual disabilities experience barriers to quality healthcare. To reduce this disparity, equipping medical trainees with the knowledge and skills required for treating this patient population is critical. Our aim is to describe the breadth of instructional interventions and identify gaps in intellectual disability medical education curricula.MethodUsing scoping review methods, the intellectual disability programmes described in 27 articles were evaluated and their coverage of the six core competencies on disability for health care education was examined.ResultsThe most frequently represented core competencies were disability conceptual frameworks, professionalism and communication, and clinical assessment, which were, in most programmes, fulfilled by activities involving individuals with intellectual disabilities. Uneven competency coverage warrants consideration.ConclusionsConsiderable variabilities exist in medical school curricula on intellectual disabilities. Using core competencies on disability for health care education for curricular design and evaluation would provide a coherent training experience in this important area.

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants. METHODS: Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living skills. The Cox Proportional Hazard model was applied to analyze differences in the probability of achievement of skills at various ages among five molecular subtypes of AS. RESULTS: Almost all individuals, regardless of molecular subtype, were able to walk with support by five years of age. By age 15, those with a deletion had at least a 50% probability of acquiring 17 out of 30 skills compared to 25 out of 30 skills among those without a deletion. Overall, fine and gross motor skills such as holding and reaching for small objects, sitting, and walking with support were achieved within a fairly narrow range of ages, while toileting, feeding, and hygiene skills tend to have greater variability in the ages at which these skills were achieved. Those without a deletion had a higher probability (25-92%) of achieving daily living skills such as independently toileting and dressing compared to those with a deletion (0-13%). Across all molecular subtypes, there was a low probability of achieving independence in bathing and brushing teeth. CONCLUSION: Individuals with AS without a deletion are more likely to achieve developmental milestones and daily living skills at an earlier age than those with a deletion. Many individuals with AS are unable to achieve daily living skills necessary for independent self-care.

PURPOSE: Clinically ascertained variants are under-utilized in neurodevelopmental disorder research. We established the Brain Gene Registry (BGR) to coregister clinically identified variants in putative brain genes with participant phenotypes. Here, we report 179 genetic variants in the first 179 BGR registrants and analyze the proportion that were novel to ClinVar at the time of entry and those that were absent in other disease databases. METHODS: From 10 academically affiliated institutions, 179 individuals with 179 variants were enrolled into the BGR. Variants were cross-referenced for previous presence in ClinVar and for presence in 6 other genetic databases. RESULTS: Of 179 variants in 76 genes, 76 (42.5%) were novel to ClinVar, and 62 (34.6%) were absent from all databases analyzed. Of the 103 variants present in ClinVar, 37 (35.9%) were uncertain (ClinVar aggregate classification of variant of uncertain significance or conflicting classifications). For 5 variants, the aggregate ClinVar classification was inconsistent with the interpretation from the BGR site-provided classification. CONCLUSION: A significant proportion of clinical variants that are novel or uncertain are not shared, limiting the evidence base for new gene-disease relationships. Registration of paired clinical genetic test results with phenotype has the potential to advance knowledge of the relationships between genes and neurodevelopmental disorders.

BACKGROUND: Disparities in colorectal cancer screening have been documented among people with intellectual and developmental disabilities (IDD). However, surgical outcomes in this population have yet to be studied. The present work aimed to evaluate the association of IDD with outcomes following colorectal cancer resection. METHODS: All adults undergoing resection for colorectal cancer in the 2011-2020 National Inpatient Sample were identified. Multivariable linear and logistic regression models were developed to examine the association of IDD with risk factors as well as outcomes including mortality, complications, costs, length of stay (LOS), and non-home discharge. The study is limited by its retrospective nature and did not capture disease staging or time of diagnosis. RESULTS: Among 722,736 patients undergoing colorectal cancer resection, 2,846 (0.39%) had IDD. Compared to patients without IDD, IDD patients were younger and had a higher burden of comorbidities. IDD status was associated with increased odds of non-elective admission (AOR 1.40 [95% CI 1.14-1.73]) and decreased odds of treatment at high-volume centers (AOR 0.64 [95% CI 0.51-0.81]). Furthermore, IDD patients experienced significantly greater LOS (9 vs 6 days, p

BackgroundIntellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living, commonly referred to as adaptive behavior (DSM-5). Although cross-sectional associations between intelligence or cognition and adaptive behavior have been reported in IDD populations, no study to date has examined whether developmental changes in cognition contribute to or track with changes in adaptive behavior. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two year period in a large sample of children, adolescents and young adults with IDD.MethodsThree groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. Eligible participants (n = 263) included those who were between 6 and 26 years (mage = 15.52, sd = 5.17) at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID, with a mental age of at least 3.0 years. Participants were given cognitive and adaptive behavior assessments at two time points over a two year period (m = 2.45 years, range = 1.27 to 5.56 years). In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid Cognition, Crystallized Cognition, Total Cognition) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization).ResultsOver a two year period, change in cognition (both Crystallized and Total Composites) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model.ConclusionsThe present study demonstrated that developmental changes in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in DLS emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, "real life" meaningfulness of changes in cognition detected by the NIHTB-CB in IDD, and provides empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the fragile X messenger ribonucleoprotein 1 (FMR1) gene due to expansion of a 5'-non-coding trinucleotide (CGG) element beyond 200 repeats (full mutation). To better understand the complex relationships among FMR1 allelotype, methylation status, mRNA expression, and FMR1 protein (FMRP) levels, FMRP was quantified in peripheral blood mononuclear cells for a large cohort of FXS (n = 154) and control (n = 139) individuals using time-resolved fluorescence resonance energy transfer. Considerable size and methylation mosaicism were observed among individuals with FXS, with FMRP detected only in the presence of such mosaicism. No sample with a minimum allele size greater than 273 CGG repeats had significant levels of FMRP. Additionally, an association was observed between FMR1 mRNA and FMRP levels in FXS samples, predominantly driven by those with the lowest FMRP values. This study underscores the complexity of FMR1 allelotypes and FMRP expression and prompts a reevaluation of FXS therapies aimed at reactivating large full mutation alleles that are likely not capable of producing sufficient FMRP to improve cognitive function.

We identified a de novo heterozygous transient receptor potential cation channel subfamily M (melastatin) member 3 (TRPM3) missense variant, p.(Asn1126Asp), in a patient with developmental delay and manifestations of cerebral palsy (CP) using phenotype-driven prioritization analysis of whole-genome sequencing data with Exomiser. The variant is localized in the functionally important ion transport domain of the TRPM3 protein and predicted to impact the protein structure. Our report adds TRPM3 to the list of Mendelian disease-associated genes that can be associated with CP and provides further evidence for the pathogenicity of the variant p.(Asn1126Asp).

BackgroundStudents with Intellectual Disability undergo frequent cognitive testing. Testing with this population is limited by insensitivity to relative strengths and weaknesses due to floor effects.AimThe study explored the utility of deviation scores via four case studies as a supplement to educational decision-making.MethodsFour students with Intellectual Disability completed cognitive testing. Deviation scores were calculated using age dependent raw z-score transformations to determine deviation from the standardization sample norms.ResultsThe application of deviation scores highlighted true relative strengths and weaknesses for students with Intellectual Disability rather than documenting previously known deficits. The four cases studies illustrated where deviation scores could, or could not, add value above and beyond traditional scoring.DiscussionDeviation scores can supplement placement and service decisions for students. Practical and psychometric considerations are reviewed.ConclusionThe findings highlight the usefulness of deviation scores in providing meaningful information to school- and clinic-based practitioners.

Eukaryotic translation elongation factor 2 (eEF2), encoded by the gene EEF2, is an essential factor involved in the elongation phase of protein translation. A specific heterozygous missense variant (p.P596H) in EEF2 was originally identified in association with autosomal dominant adult-onset spinocerebellar ataxia-26 (SCA26). More recently, additional heterozygous missense variants in this gene have been described to cause a novel, childhood-onset neurodevelopmental disorder with benign external hydrocephalus. Herein, we report two unrelated individuals with a similar gene-disease correlation to support this latter observation. Patient 1 is a 7-year-old male with a previously reported, de novo missense variant (p.V28M) who has motor and speech delay, autism spectrum disorder, failure to thrive with relative macrocephaly, unilateral microphthalmia with coloboma and eczema. Patient 2 is a 4-year-old female with a novel de novo nonsense variant (p.Q145X) with motor and speech delay, hypotonia, macrocephaly with benign ventricular enlargement, and keratosis pilaris. These additional cases help to further expand the genotypic and phenotypic spectrum of this newly described EEF2-related neurodevelopmental syndrome.

PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

Among the many race-based health disparities that have persistently plagued the US population,1 the disproportionate burden of adverse neurodevelopmental outcomes to Black children affected by autism spectrum disorder (ASD) is particularly devastating given its major lifelong consequences. Recently, in 3 successive reports from the Autism and Developmental Disabilities Monitoring (ADDM) program of the US Centers for Disease Control and Prevention (CDC) (birth cohort years 2014, 2016, and 2018), we and our collaborators reported that although the prevalence of community-diagnosed ASD had equalized for Black and non-Hispanic White (NHW) children in the United States, there has persisted a pronounced racial disparity in the proportion of ASD-affected children with comorbid intellectual disability (ID), on the order of 50% for Black children with ASD vs 20% for White children with ASD.2 Here, we provide data to support the following: much earlier diagnosis is possible; early diagnosis alone is not likely to close the ID comorbidity disparity; and judicious efforts over care as usual are necessary to ensure that Black children have access to timely implementation of developmental therapy, for which we observed promising associations with improved cognitive and adaptive outcomes in our sample.

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical in vivo approaches, we find that parvalbumin (PV) INs and their immature precursors are hypoactive and transiently decoupled from excitatory neurons in postnatal mouse somatosensory cortex (S1) of Fmr1 KO mice, a model of fragile X syndrome (FXS). This leads to a loss of parvalbumin INs (PV-INs) in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1 KO mice restores PV-IN density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering an allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs.

BackgroundFragile X syndrome (FXS) and fetal alcohol syndrome disorders are both common causes of intellectual disability in children. When both conditions are present in the same individual, the resultant phenotype may make identification of clinical issues and management challenging.Case presentationIn this case report, we present a case of triplets who had significant in utero alcohol exposure; 2 of whom also have FXS and the other not having the fragile X mutation. The siblings with FXS have subtle differences in the physical phenotype compared with the other one, who has prominent features of partial fetal alcohol syndrome instead. However, all 3 siblings have intellectual impairment (although this is more severe in the 2 with FXS), meet diagnostic criteria for autism spectrum disorder, and present with severe behavioral challenges. The clinical presentation of the 2 siblings with FXS is much more severe as compared to a child with FXS alone, and this is likely due to the additive effect of in utero alcohol exposure and environmental factors. We discuss the combination of these 2 pathologies and how this can affect the overall clinical presentation.ConclusionIn the management of children with FXS, evaluation for other risk factors that can have neurobehavioral sequelae is important, and these can affect clinical presentation and prognosis.

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense, including the recurrent p.Val44Met in 7/17 individuals, or in-frame, all affecting conserved residues located in transmembrane regions of the protein. In 12 individuals, hematological abnormalities co-occurred, such as macrocytosis and hemolysis, requiring blood transfusions in some. We modeled six variants (p.Val44Met, p.Arg433His, p.Thr481Asn, p.Gly580Ser, p.Arg660Thr, and p.Phe697Leu), each affecting a distinct transmembrane domain of the channel, in transfected Neuro2a cells and demonstrated inward leak cation currents across the mutated channel even in isotonic conditions, while the response to hypo-osmotic challenge was impaired, as were the Ca2+ transients generated under hypo-osmotic stimulation. Ectopic expression of the p.Val44Met and p.Gly580Cys variants in Drosophila resulted in early death. TMEM63B-associated DEE represents a recognizable clinicopathological entity in which altered cation conductivity results in a severe neurological phenotype with progressive brain damage and early-onset epilepsy associated with hematological abnormalities in most individuals.

The 16p11.2 and 22q11.2 copy number variants (CNVs) are associated with neurobehavioral traits including autism spectrum disorder (ASD), schizophrenia, bipolar disorder, obesity, and intellectual disability. Identifying specific genes contributing to each disorder and dissecting the architecture of CNV-trait association has been difficult, inspiring hypotheses of more complex models, such as multiple genes acting together. Using multi-tissue data from the GTEx consortium, we generated pairwise expression imputation models for CNV genes and then applied these elastic net models to GWAS for: ASD, bipolar disorder, schizophrenia, BMI (obesity), and IQ (intellectual disability). We compared the variance in these five traits explained by gene pairs with the variance explained by single genes and by traditional interaction models. We also modeled polygene region-wide effects using summed predicted expression ranks across many genes to create a regionwide score. We found that in all CNV-trait pairs except for bipolar disorder at 22q11.2, pairwise effects explain more variance than single genes. Pairwise model superiority was specific to the CNV region for all 16p11.2 traits and ASD at 22q11.2. We identified novel individual genes over-represented in top pairs that did not show single-gene signal. We also found that BMI and IQ have significant regionwide association with both CNV regions. Overall, we observe that genetic architecture differs by trait and region, but 9/10 CNV-trait combinations demonstrate evidence for multigene contribution, and for most of these, the importance of combinatorial models appears unique to CNV regions. Our results suggest that mechanistic insights for CNV pathology may require combinational models.

ASXL1 (additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression. De novo protein-truncating mutations in ASXL1 cause Bohring-Opitz syndrome (BOS; OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, distinctive facial features, hypertrichosis, increased risk of Wilms tumor, and variable congenital anomalies, including heart defects and severe skeletal defects giving rise to a typical BOS posture. These BOS-causing ASXL1 variants are also high-prevalence somatic driver mutations in acute myeloid leukemia. We used primary cells from individuals with BOS (n = 18) and controls (n = 49) to dissect gene regulatory changes caused by ASXL1 mutations using comprehensive multiomics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data show that regardless of cell type, ASXL1 mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome. The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation of VANGL2, which encodes a planar cell polarity pathway protein that acts through noncanonical Wnt signaling to direct tissue patterning and cell migration. This multiomics approach identifies the core impact of ASXL1 mutations and therapeutic targets for BOS and myeloid leukemias.

BACKGROUND: Parenting children and young adults with intellectual disabilities, including individuals with fragile X syndrome and Down syndrome, is challenging, joyful, and complicated. Exploring how parents talk about their children, and the quality of the parent/child relationship can provide insight into the home environment and interactional patterns of the family. METHOD: Expressed emotion (EE) is a measurement of a familys emotional climate based on a parent or caregivers report of warmth, emotional overinvolvement, hostility, and criticism. The purpose of this study was to describe EE for a sample of parents of individuals with intellectual disabilities and to determine any differences in EE amongst individuals within subgroups. Based on previous research about fragile X syndrome and family systems, we hypothesized that there would be significant differences between the disability groups (higher EE in families with children/young adults with fragile X syndrome). RESULTS: Results showed relatively high proportions of EE across groups of individuals with intellectual disabilities, however, there were no significant differences between the subgroups. Null findings suggest that differences in EE may not relate directly to a childs specific genetic condition. Rather, increased EE in caregiver populations may simply reflect well-documented stressors related to stigma, caregiver burden, and limited community supports. Critical statements were infrequent, however, over half of the participants reported dissatisfaction with their situation, and many were categorized as having emotional overinvolvement, as measured by frequent statements of intense worry and self-sacrifice. CONCLUSION: Findings point to potential utility in family-level interventions focused on providing structured caregiver therapy to manage excessive worry and grief related to a diagnosis of intellectual disability, and respite care to encourage caregiver independence and pursuit of personal care.

Background and objectiveIndividuals with intellectual disability (ID) experience protracted cognitive development compared with typical youth. Sensitive measurement of cognitive change in this population is a critical need for clinical trials and other intervention studies, but well-validated outcome measures are scarce. This study's aim was to evaluate the sensitivity of the NIH Toolbox Cognition Battery (NIHTB-CB) to detect developmental changes in groups with ID-fragile X syndrome (FXS), Down syndrome (DS), and other ID (OID)-and to provide further support for its use as an outcome measure for treatment trials.MethodsWe administered the NIHTB-CB and a reference standard cross-validation measure (Stanford-Binet Intelligence Scales, Fifth Edition [SB5]) to 256 individuals with FXS, DS, and OID (ages 6-27 years). After 2 years of development, we retested 197 individuals. Group developmental changes in each cognitive domain of the NIHTB-CB and SB5 were assessed using latent change score models, and 2-year growth was evaluated at 3 age points (10, 16, and 22 years).ResultsOverall, effect sizes of growth measured by the NIHTB-CB tests were comparable with or exceeded those of the SB5. The NIHTB-CB showed significant gains in almost all domains in OID at younger ages (10 years), with continued gains at 16 years and stability in early adulthood (22 years). The FXS group showed delayed gains in attention and inhibitory control compared with OID. The DS group had delayed gains in receptive vocabulary compared with OID. Unlike the other groups, DS had significant growth in early adulthood in 2 domains (working memory and attention/inhibitory control). Notably, each group's pattern of NIHTB-CB growth across development corresponded to their respective pattern of SB5 growth.DiscussionThe NIHTB-CB is sensitive to developmental changes in individuals with ID. Comparison with levels and timing of growth on the cross-validation measure shows that the NIHTB-CB has potential to identify meaningful trajectories across cognitive domains and ID etiologies. Sensitivity to change within the context of treatment studies and delineation of clinically meaningful changes in NIHTB-CB scores, linked to daily functioning, must be established in future research to evaluate the battery more completely as a key outcome measure.

BACKGROUND: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimers disease (AD). OBJECTIVE: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site. METHODS: Analyses involved adults with DS from the Alzheimers Biomarkers Consortium-Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was based on IQ or mental age scores prior to dementia concerns. PET was acquired using [11C] PiB for Aβ, and [18F] AV-1451 for tau. RESULTS: Cognitive data was available for 361 participants with a mean age of 45.22 (SD = 9.92) and PET biomarker data was available for 154 participants. There was not a significant effect of premorbid ID level by age on cognitive outcomes. There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET. There was not a significant difference in age at time of study visit of those with mild cognitive impairment-DS or dementia by premorbid ID level. CONCLUSION: Findings provide robust evidence of a similar time course in AD trajectory across premorbid ID levels, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials.

Fragile X syndrome is caused by the expansion of CGG triplets in the FMR1 gene, which generates epigenetic changes that silence its expression. The absence of the protein coded by this gene, FMRP, causes cellular dysfunction, leading to impaired brain development and functional abnormalities. The physical and neurologic manifestations of the disease appear early in life and may suggest the diagnosis. However, it must be confirmed by molecular tests. It affects multiple areas of daily living and greatly burdens the affected individuals and their families. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism spectrum disorder; the diagnosis should be suspected in every patient with neurodevelopmental delay. Early interventions could improve the functional prognosis of patients with Fragile X syndrome, significantly impacting their quality of life and daily functioning. Therefore, healthcare for children with Fragile X syndrome should include a multidisciplinary approach.

BackgroundUnbalanced translocations can cause developmental delay (DD), intellectual disability (ID), growth problems, dysmorphic features, and congenital anomalies. They may arise de novo or may be inherited from a parent carrying a balanced rearrangement. It is estimated that 1/500 people is a balanced translocation carrier. The outcomes of different chromosomal rearrangements have the potential to reveal the functional consequences of partial trisomy or partial monosomy and can help guide genetic counseling for balanced carriers, and other young patients diagnosed with similar imbalances.MethodsWe performed clinical phenotyping and cytogenetic analyses of two siblings with a history of developmental delay (DD), intellectual disability (ID) and dysmorphic features.ResultsThe proband, a 38-year-old female, has a history of short stature, dysmorphic features and aortic coarctation. She underwent chromosomal microarray analysis, which identified partial monosomy of 4q and partial trisomy of 10p. Her brother, a 37-year-old male, has a history of more severe DD, behavioral problems, dysmorphic features, and congenital anomalies. Subsequently, karyotype confirmed two different unbalanced translocations in the siblings: 46,XX,der(4)t(4;10)(q33;p15.1) and 46,XY,der(10)t(4;10)(q33;p15.1), respectively. These chromosomal rearrangements represent two possible outcomes from a parent who is a carrier for a balanced translocation 46,XX,t(4;10)(q33;p15.1).ConclusionTo our knowledge, this 4q and 10p translocation has not been described in literature. In this report we compare clinical features due to the composite effects of partial monosomy 4q with partial trisomy 10p and partial trisomy 4q with partial monosomy 10p. These findings speak to the relevance of old and new genomic testing, the viability of these segregation outcomes, and need for genetic counseling.

BackgroundIntellectual disability affects approximately one third of individuals with autism spectrum disorder (autism). Yet, a major unresolved neurobiological question is what differentiates autistic individuals with and without intellectual disability. Intelligence quotients (IQs) are highly variable during childhood. We previously identified three subgroups of autistic children with different trajectories of intellectual development from early (2-3½ years) to middle childhood (9-12 years): (a) persistently high: individuals whose IQs remained in the normal range; (b) persistently low: individuals whose IQs remained in the range of intellectual disability (IQ < 70); and (c) changers: individuals whose IQs began in the range of intellectual disability but increased to the normal IQ range. The frontoparietal (FPN) and default mode (DMN) networks have established links to intellectual functioning. Here, we tested whether brain regions within the FPN and DMN differed volumetrically between these IQ trajectory groups in early childhood.MethodsWe conducted multivariate distance matrix regression to examine the brain regions within the FPN (11 regions x 2 hemispheres) and the DMN (12 regions x 2 hemispheres) in 48 persistently high (18 female), 108 persistently low (32 female), and 109 changers (39 female) using structural MRI acquired at baseline. FPN and DMN regions were defined using networks identified in Smith et al. (Proc Natl Acad Sci U S A 106:13040-5, 2009). IQ trajectory groups were defined by IQ measurements from up to three time points spanning early to middle childhood (mean age time 1: 3.2 years; time 2: 5.4 years; time 3: 11.3 years).ResultsThe changers group exhibited volumetric differences in the DMN compared to both the persistently low and persistently high groups at time 1. However, the persistently high group did not differ from the persistently low group, suggesting that DMN structure may be an early predictor for change in IQ trajectory. In contrast, the persistently high group exhibited differences in the FPN compared to both the persistently low and changers groups, suggesting differences related more to concurrent IQ and the absence of intellectual disability.ConclusionsWithin autism, volumetric differences of brain regions within the DMN in early childhood may differentiate individuals with persistently low IQ from those with low IQ that improves through childhood. Structural differences in brain networks between these three IQ-based subgroups highlight distinct neural underpinnings of these autism sub-phenotypes.

The recent National Institute of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) initiative has bolstered capacity for the current increase in clinical trials involving individuals with Down syndrome (DS). This new NIH funding mechanism offers new opportunities to expand and develop novel approaches in engaging and effectively enrolling a broader representation of clinical trials participants addressing current medical issues faced by individuals with DS. To address this opportunity, the NIH assembled leading clinicians, scientists, and representatives of advocacy groups to review existing methods and to identify those areas where new approaches are needed to engage and prepare DS populations for participation in clinical trial research. This paper summarizes the results of the Clinical Trial Readiness Working Group that was part of the INCLUDE Project Workshop: Planning a Virtual Down Syndrome Cohort Across the Lifespan Workshop held virtually September 23 and 24, 2019.

Maternal autoantibody-related ASD (MAR ASD) is a subtype of autism in which pathogenic maternal autoantibodies (IgG) cross the placenta, access the developing brain, and cause neurodevelopmental alterations and behaviors associated with autism in the exposed offspring. We previously reported maternal IgG response to eight proteins (CRMP1, CRMP2, GDA LDHA, LDHB, NSE, STIP1, and YBOX) and that reactivity to nine specific combinations of these proteins (MAR ASD patterns) was predictive of ASD risk. The aim of the current study was to validate the previously identified MAR ASD patterns (CRMP1 + GDA, CRMP1 + CRMP2, NSE + STIP1, CRMP2 + STIP1, LDHA + YBOX, LDHB + YBOX, GDA + YBOX, STIP1 + YBOX, and CRMP1 + STIP1) and their accuracy in predicting ASD risk in a prospective cohort employing maternal samples collected prior to parturition. We used prenatal plasma from mothers of autistic children with or without co-occurring intellectual disability (ASD = 540), intellectual disability without autism (ID = 184) and general population controls (GP = 420) collected by the Early Markers for Autism (EMA) study. We found reactivity to one or more of the nine previously identified MAR ASD patterns in 10% of the ASD group compared with 4% of the ID group and 1% of the GP controls (ASD vs GP: Odds Ratio (OR) = 7.81, 95% Confidence Interval (CI) 3.32 to 22.43; ASD vs ID: OR = 2.77, 95% CI (1.19-7.47)) demonstrating that the MAR ASD patterns are strongly associated with the ASD group and could be used to assess ASD risk prior to symptom onset. The pattern most strongly associated with ASD was CRMP1 + CRMP2 and increased the odds for an ASD diagnosis 16-fold (3.32 to >999.99). In addition, we found that several of these specific MAR ASD patterns were strongly associated with ASD with intellectual disability (ASD + ID) and others associated with ASD without ID (ASD-no ID). Prenatal screening for these MAR patterns may lead to earlier identification of ASD and facilitate access to the appropriate early intervention services based on each child's needs.

This pilot study sought to identify potential markers of improvement from pre-post treatment in response to computerized working memory (WM) training for youth (ages 8-18) with autism spectrum disorder (ASD) and comorbid intellectual disability (ID) in a single arm, pre-post design. Participants included 26 children with ASD and 18 with comorbid ASD and fragile X syndrome (ASD+FXS). Analyses were adjusted for age and IQ. The ASD group demonstrated greater improvement on WM training relative to the ASD+FXS group. Participants improved on WM and far transfer outcomes, however, there were no significant group differences in improvement except for repetitive behavior. Higher hyperactivity/impulsivity ratings predicted lower performance on visuospatial WM. Findings suggest cognitive training may be beneficial for youth with ASD and ID, warranting further exploration.

BackgroundO'Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O'Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.MethodsAffected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.ResultsWe report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.ConclusionOur study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.

The additional sex combs-like (ASXL) gene family-encoded by ASXL1, ASXL2, and ASXL3-is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina's Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath's epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes.

The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5' and 3' splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction with splice sites. We identified biallelic pathogenic variants in FRA10AC1 in five individuals from three consanguineous families. The two unrelated Patients 1 and 2 with loss-of-function variants showed developmental delay, intellectual disability, and no speech, while three siblings with the c.494_496delAAG (p.Glu165del) variant had borderline to mild intellectual disability. All patients had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. FRA10AC1 transcripts and proteins were drastically reduced or absent in fibroblasts of Patients 1 and 2. In a heterologous expression system, the p.Glu165del variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localization. By co-immunoprecipitation, we found ectopically expressed HA-FRA10AC1 in complex with endogenous DGCR14, another component of the spliceosomal C complex, while the splice factors CHERP, NKAP, RED, and SF3B2 could not be co-immunoprecipitated. Using an in vitro splicing reporter assay, we did not obtain evidence for FRA10AC1 deficiency to suppress missplicing events caused by mutations in the highly conserved dinucleotides of 5' and 3' splice sites in an in vitro splicing assay in patient-derived fibroblasts. Our data highlight the importance of specific peripheral spliceosomal C complex proteins for neurodevelopment. It remains possible that FRA10AC1 may have other and/or additional cellular functions, such as coupling of transcription and splicing reactions.

This study characterized the rates of attention-deficit/hyperactivity disorder (ADHD) in adolescent and young adult males with fragile X syndrome (FXS) using a multi-method approach integrating a DSM-based parent interview (Children's Interview for Psychiatric Syndromes; P-ChIPS, Fristad et al., 1998) and a parent rating scale (Child Behavior Checklist; CBCL, Achenbach, 2001). Thirty-one males with FXS, aged 16-24 years, participated. Forty-two percent met DSM-5 criteria for ADHD and 35% exceeded the CBCL cut-offs. Agreement between the two classification methods was fair (κ = 0.38). Autism symptom severity and nonverbal cognitive ability did not predict ADHD diagnoses/symptoms. Results show high rates of ADHD in males with FXS during late adolescence and young adulthood, which are not accounted for by impaired nonverbal cognitive skills or autism symptom severity. DSM-based ADHD-specific scales are recommended over broadband symptom scales to improve accurate identification.

The ARID1A gene is an infrequent cause of Coffin-Siris syndrome (CSS) and has been associated with severe to profound developmental delays and hypotonia in addition to characteristic craniofacial and digital findings. We present three fetuses and a male neonate with ventriculomegaly/hydrocephalus, absence of the corpus callosum (ACC), cerebellar hypoplasia, retinal dysplasia, lung lobulation defects, renal dysplasia, imperforate or anteriorly placed anus, thymus hypoplasia and a single umbilical artery. Facial anomalies included downslanting palpebral fissures, wide-spaced eyes, low-set and posteriorly rotated ears, a small jaw, widely spaced nipples and hypoplastic nails. All fetuses had heterozygous variants predicting premature protein truncation in ARID1A (c.4886dup:p.Val1630Cysfs*18; c.4860dup:p.Pro1621Thrfs*27; and c.175G>T:p.Glu59*) and the baby's microarray demonstrated mosaicism for a deletion at chromosome 1p36.11 (arr[GRCh37] 1p36.11(26,797,508_27,052,080)×1∼2), that contained the first exon of ARID1A. Although malformations, in particular ACC, have been described with CSS caused by pathogenic variants in ARID1A, prenatal presentations associated with this gene are rare. Retinal dysplasia, lung lobulation defects and absent thymus were novel findings in association with ARID1A variants. Studies in cancer have demonstrated that pathogenic ARID1A variants hamper nuclear import of the protein and/or affect interaction with the subunits of SWI/SNF complex, resulting in dysregulation of the PI3K/AKT pathway and perturbed PTEN and PIKC3A signaling. As haploinsufficiency for PTEN and PIKC3A can be associated with ventriculomegaly/hydrocephalus, aberrant expression of these genes is a putative mechanism for the brain malformations demonstrated in patients with ARID1A variants.

Those with Down syndrome (DS)-trisomy for chromosome 21-are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.

Speeded Matching (SpM) is a new processing speed match-to-sample test within the NIH Toolbox Cognitive Battery. It was designed to developmentally extend feasibility to younger children or individuals with intellectual or developmental disabilities (IDD). SpM reduces cognitive demands to tapping an identical match as opposed to judging and indicating whether two stimuli are identical. In this study, we piloted SpM among 148 participants with fragile X syndrome, Down syndrome, or other intellectual disabilities (chronological age mean = 17.8 years, sd = 5.4; nonverbal mental age mean = 65 months, sd = 19.4). SpM had a high feasibility (96%) and internal consistency (rxx = 0.98). It converged well with other measures of processing speed, fluid cognition, and nonverbal mental age and diverged appropriately from crystallized cognitive skills. The correlation between nonverbal mental age and SpM in the IDD sample was not significantly different than the correlation between chronological age and SpM in a separate sample of 118 neurotypical children (age mean = 3.9 years sd = 0.8). This study provides initial evidence for the reliability and validity of the new SpM task, which may be appropriate as an outcome measure of processing speed for future clinical trials. It is more feasible than tasks designed for adults; it is brief, easy to administer, and engaging for young children and older individuals with lower mental ages associated with IDD.

Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.

Fragile X syndrome (FXS) is an inherited genetic condition that is the leading known cause of inherited intellectual developmental disability. Phenotypically, individuals with FXS also present with distinct physical features including, elongated face, prominent ears, pectus excavatum, macroorchidism, and joint laxity, which suggests connective tissue dysplasia. In addition to mitral valve prolapse, aortic dilatation has been identified within individuals with FXS. Abnormal elastin fiber networks have been found in the skin, valves, and aorta in individual cases. Aortic dilatation has been described in other connective tissue disorders, particularly Marfan syndrome. However, while aortic aneurysms are characteristic of Marfan syndrome, no similar cases have been reported in FXS patients to date. This case report details the presentation of two patients with FXS and aortic aneurysm. Our two cases highlight the risks of aortic pathology in FXS, and the need for monitoring in asymptomatic patients with significant aortic dilatation.

Caregiver reports, clinical observations, and diagnostic assessments indicate that most individuals with fragile X syndrome experience high levels of chronic anxiety. However, anxiety is a challenging endpoint for outcome measurement in FXS because most individuals cannot reliably report internal emotional or body states. A comprehensive survey of the presence, frequency, and duration of anxiety-related symptoms and questions to elicit open-ended responses was completed by caregivers of 456 individuals with FXS, ages 2-81 years (87 female, 369 male) and 24 female and 2 male FXS self-advocates ages 15-66 years. Caregivers reported classic behavioral indicators of anxiety, such as avoidance, irritability, motor agitation, and physiological symptoms, as well as behavioral features in FXS such as repetitive behavior, aggression, and self-injury. Self-advocate accounts largely paralleled caregiver data. Factor analyses yielded four factors: (1) increased irritability, aggression, and self-injury; (2) increased physical movement, nervous activity, and restlessness; (3) physical and physiological features of anxiety; and (4) internalizing and gastrointestinal symptoms. Caregivers are capable of observing and reporting behaviors that are valid indicators of anxious states that are usually reported in self-report standardized assessments. These results support the development of an anxiety measure for FXS that minimizes problems with rater inference.

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.

The fragile X mental retardation (FMR1) gene contains an expansion-prone CGG repeat within its 5' UTR. Alleles with 55-200 repeats are known as premutation (PM) alleles and confer risk for one or more of the FMR1 premutation (PM) disorders that include Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-Associated Neuropsychiatric Disorders (FXAND). PM alleles expand on intergenerational transmission, with the children of PM mothers being at risk of inheriting alleles with > 200 CGG repeats (full mutation FM) alleles) and thus developing Fragile X Syndrome (FXS). PM alleles can be somatically unstable. This can lead to individuals being mosaic for multiple size alleles. Here, we describe a detailed evaluation of somatic mosaicism in a large cohort of female PM carriers and show that 94% display some evidence of somatic instability with the presence of a series of expanded alleles that differ from the next allele by a single repeat unit. Using two different metrics for instability that we have developed, we show that, as with intergenerational instability, there is a direct relationship between the extent of somatic expansion and the number of CGG repeats in the originally inherited allele and an inverse relationship with the number of AGG interruptions. Expansions are progressive as evidenced by a positive correlation with age and by examination of blood samples from the same individual taken at different time points. Our data also suggests the existence of other genetic or environmental factors that affect the extent of somatic expansion. Importantly, the analysis of candidate single nucleotide polymorphisms (SNPs) suggests that two DNA repair factors, FAN1 and MSH3, may be modifiers of somatic expansion risk in the PM population as observed in other repeat expansion disorders.

Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, we derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome carrying clinically relevant mutations in TCF4. We show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons. We identify a mechanism through which TCF4 loss-of-function leads to decreased Wnt signaling and then to diminished expression of SOX genes, culminating in reduced progenitor proliferation in vitro. Moreover, we show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signaling. This work delineates pathological mechanisms in neural cells harboring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.

Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants" a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants.

BackgroundGenetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of individual exons in the developing human brain.MethodsRNA-seq data from 783 human brain samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples.ResultsIn the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A, SCN3A, and SCN8A, a brain-wide synchronized 5N to 5A transition occurs between 24 post-conceptual weeks (2nd trimester) and 6 years of age. In mice, the equivalent 5N to 5A transition begins at or before embryonic day 15.5. In SCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories.ConclusionsExon usage in SCN1A, SCN2A, SCN3A, and SCN8A changes dramatically during human brain development. These splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.

BackgroundDeletions and duplications of the multigenic 16p11.2 and 22q11.2 copy number variant (CNV) regions are associated with brain-related disorders including schizophrenia, intellectual disability, obesity, bipolar disorder, and autism spectrum disorder (ASD). The contribution of individual CNV genes to each of these identified phenotypes is unknown, as well as the contribution of these CNV genes to other potentially subtler health implications for carriers. Hypothesizing that DNA copy number exerts most effects via impacts on RNA expression, we attempted a novel in silico fine-mapping approach in non-CNV carriers using both GWAS and biobank data.MethodsWe first asked whether gene expression level in any individual gene in the CNV region alters risk for a known CNV-associated behavioral phenotype(s). Using transcriptomic imputation, we performed association testing for CNV genes within large genotyped cohorts for schizophrenia, IQ, BMI, bipolar disorder, and ASD. Second, we used a biobank containing electronic health data to compare the medical phenome of CNV carriers to controls within 700,000 individuals in order to investigate the full spectrum of health effects of the CNVs. Third, we used genotypes for over 48,000 individuals within the biobank to perform phenome-wide association studies between imputed expressions of individual 16p11.2 and 22q11.2 genes and over 1500 health traits.ResultsUsing large genotyped cohorts, we found individual genes within 16p11.2 associated with schizophrenia (TMEM219, INO80E, YPEL3), BMI (TMEM219, SPN, TAOK2, INO80E), and IQ (SPN), using conditional analysis to identify upregulation of INO80E as the driver of schizophrenia, and downregulation of SPN and INO80E as increasing BMI. We identified both novel and previously observed over-represented traits within the electronic health records of 16p11.2 and 22q11.2 CNV carriers. In the phenome-wide association study, we found seventeen significant gene-trait pairs, including psychosis (NPIPB11, SLX1B) and mood disorders (SCARF2), and overall enrichment of mental traits.ConclusionsOur results demonstrate how integration of genetic and clinical data aids in understanding CNV gene function and implicates pleiotropy and multigenicity in CNV biology.

BackgroundRecent large-scale initiatives have led to systematically collected phenotypic data for several rare genetic conditions implicated in autism spectrum disorder (ASD). The onset of developmentally expected skills (e.g. walking, talking) serve as readily quantifiable aspects of the behavioral phenotype. This study's aims were: (a) describe the distribution of ages of attainment of gross motor and expressive language milestones in several rare genetic conditions, and (b) characterize the likelihood of delays in these conditions compared with idiopathic ASD.MethodsParticipants aged 3 years and older were drawn from two Simons Foundation Autism Research Initiative registries that employed consistent phenotyping protocols. Inclusion criteria were a confirmed genetic diagnosis of one of 16 genetic conditions (Simons Searchlight) or absence of known pathogenic genetic findings in individuals with ASD (SPARK). Parent-reported age of acquisition of three gross motor and two expressive language milestones was described and categorized as on-time or delayed, relative to normative expectations.ResultsDevelopmental milestone profiles of probands with genetic conditions were marked by extensive delays (including nonattainment), with highest severity in single gene conditions and more delays than idiopathic ASD in motor skills. Compared with idiopathic ASD, the median odds of delay among the genetic groups were higher by 8.3 times (IQR 5.8-16.3) for sitting, 12.4 times (IQR 5.3-19.5) for crawling, 26.8 times (IQR 7.7-41.1) for walking, 2.7 times (IQR 1.7-5.5) for single words, and 5.7 times (IQR 2.7-18.3) for combined words.ConclusionsDelays in developmental milestones, particularly in gross motor skills, are frequent and may be among the earliest indicators of differentially affected developmental processes in specific genetically defined conditions associated with ASD, as compared with those with clinical diagnoses of idiopathic ASD. The possibility of different developmental pathways leading to ASD-associated phenotypes should be considered when deciding how to employ specific genetic conditions as models for ASD.

BackgroundScant data exist on weight loss interventions for youth with intellectual disabilities (ID).ObjectiveTo compare weight loss among youth with ID randomized to a 6-month, family-based behavioural intervention (FBBI) or a waitlist and to compare weight loss among youth who completed a 6-month maintenance (FBBI-M) intervention to a control group (FBBI-C).MethodsYouth with ID and overweight/obesity, aged 14-22 years, were randomized to the FBBI or to a waitlist and subsequently randomized to a maintenance intervention or a control group. Sessions were held weekly during the FBBI and biweekly during the FBBI-M. Using an intention-to-treat approach, we used linear mixed models to test differences in the change in weight and in BMI from the start of FBBI.ResultsThe 24 participants who received the FBBI lost, on average (SE), 5.1 (1.1) kg (P

Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because symptoms are overshadowed by the intellectual disability associated with Down syndrome. In people with Down syndrome, fluid and imaging biomarkers have shown good diagnostic performances and a strikingly similar temporality of changes with respect to sporadic and autosomal dominant Alzheimer's disease. Most importantly, there are no treatments to prevent Alzheimer's disease, even though adults with Down syndrome could be an optimal population in whom to conduct Alzheimer's disease prevention trials. Unprecedented research activity in Down syndrome is rapidly changing this bleak scenario that will translate into disease-modifying therapies that could benefit other populations.

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.

BackgroundDelayed walking is common in intellectual disability (ID) but may be less common when ID occurs with autism spectrum disorder (ASD). Previous studies examining this were limited by reliance on clinical samples and exclusion of children with severe motor deficits.ObjectiveTo examine in a population-based sample if age of walking is differentially related to intellectual ability in children with ASD versus other neurodevelopmental disorders (NDD).MethodsParticipants were from the nested Autism Birth Cohort Study of the Norwegian Mother, Father and Child Cohort Study (MoBa). Cox proportional hazards regression assessed if diagnosis (ASD n = 212 vs. NDD n = 354), continuous nonverbal IQ, and their interaction, were associated with continuous age of walking.ResultsThe relationship between nonverbal IQ and age of walking was stronger for NDD than for ASD (Group × nonverbal IQ interaction, χ2  = 13.93, p = .0002). This interaction was characterized by a 21% decrease in the likelihood of walking onset at any given time during the observation period per 10-point decrease in nonverbal IQ (hazard ratio = 0.79, 95% CI: 0.78-0.85) in the NDD group compared to 8% (hazard ratio = 0.92, 95% CI: 0.86-0.98) in the ASD group.ConclusionsThe finding that age of walking is less strongly related to low intellectual ability in children with ASD than in children without other NDDs supports the hypothesis that ID in ASD may result from heterogeneous developmental pathways. Late walking may be a useful stratification variable in etiological research focused on ASD and other NDDs.

The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.

BackgroundAdults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and establish longitudinal changes in adults with Down syndrome.MethodsWe did a multicentre cohort study, including adults with Down syndrome (≥18 years), recruited from six hospitals and university medical centres in France, Germany, Spain, the UK, and the USA, who had been assessed, followed up, and provided at least two plasma samples. Participants were classified by local clinicians, who were masked to biomarker data, as asymptomatic (ie, no clinical suspicion of Alzheimer's disease), prodromal Alzheimer's disease, or Alzheimer's disease dementia. We classified individuals who progressed along the Alzheimer's disease continuum during follow-up as progressors. Plasma samples were analysed retrospectively; NfL concentrations were measured centrally using commercial kits for biomarker detection. We used ANOVA to evaluate differences in baseline NfL concentrations, Cox regression to study their prognostic value, and linear mixed models to estimate longitudinal changes. To account for potential confounders, we included age, sex, and intellectual disability as covariates in the analyses.FindingsBetween Aug 2, 2010, and July 16, 2019, we analysed 608 samples from 236 people with Down syndrome: 165 (70%) were asymptomatic, 32 (14%) had prodromal Alzheimer's disease, and 29 (12%) had Alzheimer's disease dementia; ten [4%] participants were excluded because their classification was uncertain. Mean follow-up was 3·6 years (SD 1·6, range 0·6-9·2). Baseline plasma NfL concentrations showed an area under the receiver operating characteristic curve of 0·83 (95% CI 0·76-0·91) in the prodromal group and 0·94 (0·90-0·97) in the dementia group for differentiating from participants who were asymptomatic. An increase of 1 pg/mL in baseline NfL concentrations was associated with a 1·04-fold risk of clinical progression (95% CI 1·01-1·07; p=0·0034). Plasma NfL concentrations showed an annual increase of 3·0% (95% CI 0·4-5·8) per year in the asymptomatic non-progressors group, 11·5% (4·9-18·5) per year in the asymptomatic progressors group, and 16·0% (8·4-24·0) per year in the prodromal Alzheimer's disease progressors group. In participants with Alzheimer's disease dementia, NfL concentrations increased by a mean of 24·3% (15·3-34·1).InterpretationPlasma NfL concentrations have excellent diagnostic and prognostic performance for symptomatic Alzheimer's disease in Down syndrome. The longitudinal trajectory of plasma NfL supports its use as a theragnostic marker in clinical trials.FundingAC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens und Umwelteinflüssen auf die menschliche Gesundheit, and NHS National Institute of Health Research Applied Research Collaborations East of England, UK.