Search

Cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing was performed to detect recurrent 1.4 Mb deletions at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD). The data provide insight into recurrent deletion of 17q12, pathogenic CNV that confers a very high risk for ASD and schizophrenia and significance of one or more of the 1S dosage sensitive genes in the deleted interval for normal brain development and function.

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1–2,000 bp upstream of the transcription start site, was highly predictive of brain-expressed genes. This signature was observed in 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After 8 days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest that functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption. [Display omitted] • ASD-associated TRs share substantial genomic binding sites in developing human and mouse cortex • The overlap within a promoter region was highly predictive of brain-expressed genes • Functional convergence of ASD-associated TRs leads to shared neurodevelopmental disorders Using NGS approaches, Fazel Darbandi et al. demonstrate that ASD-associated TRs in the developing cortex share substantial overlap in their binding sites. In vitro CRISPRi delineated downstream convergent biology that correlates with the postmortem brain samples from individuals with ASD. We suggest that functional convergence of ASD-associated TRs leads to shared neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Technological advances have enabled high-throughput omics assays, such as parallelized screening of lipids across plasma samples. Pioneering a new paradigm for neuropsychiatric biomarker discovery, Yap et al. describe a large-scale systematic analysis of comprehensive phenotypic, genotypic, environmental, and lipidomic data to unravel the intricate interplay between these and autism-associated traits. [ABSTRACT FROM AUTHOR]

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel Na V 1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A -related disorders. [ABSTRACT FROM AUTHOR]

Neuroscientists are increasingly using advanced neuroimaging methods to elucidate the intergenerational transmission of human brain circuitry. This new line of work promises to shed light on the ontogeny of complex behavioral traits, including psychiatric disorders, and possible mechanisms of transmission. Here we highlight recent intergenerational neuroimaging studies and provide recommendations for future work. [ABSTRACT FROM AUTHOR]

Posttranscriptional RNA modifications by adenosine-to-inosine (A-to-I) editing are abundant in the brain, yet elucidating functional sites remains challenging. To bridge this gap, we investigate spatiotemporal and genetically regulated A-to-I editing sites across prenatal and postnatal stages of human brain development. More than 10,000 spatiotemporally regulated A-to-I sites were identified that occur predominately in 3′ UTRs and introns, as well as 37 sites that recode amino acids in protein coding regions with precise changes in editing levels across development. Hyper-edited transcripts are also enriched in the aging brain and stabilize RNA secondary structures. These features are conserved in murine and non-human primate models of neurodevelopment. Finally, thousands of cis -editing quantitative trait loci (edQTLs) were identified with unique regulatory effects during prenatal and postnatal development. Collectively, this work offers a resolved atlas linking spatiotemporal variation in editing levels to genetic regulatory effects throughout distinct stages of brain maturation. [Display omitted] • Alu editing activity is tightly regulated and increases across neurodevelopment • Spatiotemporally regulated sites in 3′ UTRs and coding regions offer functional insights • Hyper-edited RNA is enriched in the aging brain and stabilizes RNA secondary structures • cis -editing quantitative trait loci have unique regulatory effects in development This resource article illuminates precise regulation of A-to-I editing throughout human brain development. These findings provide an atlas of spatiotemporally and genetically regulated A-to-I sites and their putative functional effects during prenatal and postnatal periods. Additional avenues to dissect the role of RNA editing in neurodevelopment are provided. [ABSTRACT FROM AUTHOR]

Rapid progress in identifying the genes underlying autism spectrum disorder (ASD) has provided the substrate for a first wave of analyses into the underlying neurobiology. This review describes the consensus across these diverse analyses, highlighting two distinct sets of genes: 1) Genes that regulate chromatin and transcription, especially in cortical projection neurons and striatal medium spiny neurons during mid-fetal development; and 2) Genes involved in synapse development and function, especially during infancy and early childhood, and differentially expressed in the post mortem ASD brain. Both gene sets are also regulatory targets of the ASD genes CHD8 and FMRP . It remains to be seen whether these represent two independent paths to the ASD phenotype or two components of a common path. [ABSTRACT FROM AUTHOR]

Background: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes. Methods: We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated. Results: While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 × 10−4 − 1.6 × 10−2), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes. Conclusions: We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders. [ABSTRACT FROM AUTHOR]

Loss-of-function variants in the gene SCN2A , which encodes the sodium channel Na V 1.2, are strongly associated with autism spectrum disorder and intellectual disability. An estimated 20%–30% of children with these variants also suffer from epilepsy, with altered neuronal activity originating in neocortex, a region where Na V 1.2 channels are expressed predominantly in excitatory pyramidal cells. This is paradoxical, as sodium channel loss in excitatory cells would be expected to dampen neocortical activity rather than promote seizure. Here, we examined pyramidal neurons lacking Na V 1.2 channels and found that they were intrinsically hyperexcitable, firing high-frequency bursts of action potentials (APs) despite decrements in AP size and speed. Compartmental modeling and dynamic-clamp recordings revealed that Na V 1.2 loss prevented potassium channels from properly repolarizing neurons between APs, increasing overall excitability by allowing neurons to reach threshold for subsequent APs more rapidly. This cell-intrinsic mechanism may, therefore, account for why SCN2A loss-of-function can paradoxically promote seizure. [Display omitted] • Conditional deletion of Na V 1.2 channels increases action potential (AP) excitability • Na V 1.2 regulates somatodendritc excitability, and Na V 1.6 regulates axonal action potential initiation • Lack of Na V 1.2 channels impairs AP repolarization by reducing K V activation • Reduced K V -mediated AP after hyperpolarization increases AP output Loss of sodium channels in individual neurons is expected to reduce neuronal excitability. Spratt and colleagues show that loss of Scn2a -encoded Na V 1.2 channels in mouse prefrontal pyramidal cells can paradoxically increase excitability due to Na V 1.2's distinct role in regulating somatodendritic excitability, independent of action potential electrogenesis in the axon. [ABSTRACT FROM AUTHOR]

Background Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. Methods Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. Results Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. Conclusions In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD. [ABSTRACT FROM AUTHOR]

Background: Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. Methods: We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. Results: Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. Conclusions: Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation. [Copyright &y& Elsevier]

Abstract: We report the clinical and cytogenetic findings on a male child with developmental language disorder, no physical abnormalities, and a balanced t(10;15)(q24.1;q21.1) translocation. As the child''s parents are unavailable for investigations, it is unclear whether the translocation is inherited or de novo. Fluorescence in situ hybridization (FISH) analyses were carried out using specific RP11-BAC clones mapping near 15q21.1 and 10q24.1 to refine the location of the breakpoints. The breakpoint on 15q21.1 interrupts the SEMA6D gene and the breakpoint on 10q24.1 is located between the ENTPD1 and CCNJ genes. The SEMA6D gene was further investigated in samples of individuals with developmental language disorders and controls; this investigation offered further evidence of the involvement of SEMA6D with developmental language disorders. [Copyright &y& Elsevier]

The article offers information on occurrence of autism among girls. Topics discussed include of male to female ratio for autism spectrum disorders (ASD); reasons for more numbers of males to suffer with ASD such as fragile X syndrome; direct investigations of sex effects in genetic studies to improve early screening and diagnostic practices and increment for risk of ASD among girls who pay attention to a social video.

Background Variants in the SCN2A gene that disrupt the encoded neuronal sodium channel Na V 1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect Na V 1.2 function and neuronal excitability are unclear. Methods We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry. Resultant data were incorporated into computational models of developing and mature cortical pyramidal cells that express Na V 1.2. Results In contrast to gain of function variants that contribute to seizure, we found that all ASD-associated variants dampened or eliminated channel function. Incorporating these electrophysiological results into a compartmental model of developing excitatory neurons demonstrated that all ASD variants, regardless of their mechanism of action, resulted in deficits in neuronal excitability. Corresponding analysis of mature neurons predicted minimal change in neuronal excitability. Conclusions This functional characterization thus identifies SCN2A mutation and Na V 1.2 dysfunction as the most frequently observed ASD risk factor detectable by exome sequencing and suggests that associated changes in neuronal excitability, particularly in developing neurons, may contribute to ASD etiology. [ABSTRACT FROM AUTHOR]