De novo variants in Chinese ASD trios reveal genetic basis underlying autism without developmental delay and intellectual disabilities

AbstractAutism spectrum disorder (ASD) is a complex neurodevelopmental disorder that causes a range of social communication and behavioral impairments. ASD typically manifests in young children, often with developmental delay or intellectual disabilities (DD/ID) as comorbidities. Accruing evidence indicates that ASD is highly heritable and genomewide studies on ASD cohorts have defined numerous genetic contributors. Notably, most of these studies have been performed with individuals of European and Hispanic ancestry and thus there is a paucity of genetic analyses of ASD in the East Asian population. Here, we performed whole-exome sequencing on 772 ASD trios from China, combining with a previous study of 369 Chinese ASD trios, to identify de novo variants in a total of 1141 ASD trios. We found that ASD probands without DD/ID carried less disruptive de novo variants, including protein-truncating and missense variants, than ASD with DD/ID. Surprisingly, we showed that expression of genes with de novo variants found in ASD probands without DD/ID were enriched in a specific group of neural progenitor cells, suggesting a potential mechanism underlying high-functioning autism. Importantly, some ASD risk genes from this study are not present in the current ASD gene database, suggesting that there are novel genetic contributors to ASD in East Asian populations. We validated one such novel ASD risk gene – SLC35G1 by showing that mice harboring heterozygous deletion of Slc35g1 exhibited defects in social interaction behaviors. Together, this work nominates novel ASD risk genes and indicates that ASD genetic studies in different geographic populations are essential to reveal the comprehensive genetic architecture of ASD.

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De novo variants in Chinese ASD trios reveal distinct genetic basis underlying autism with and without developmental delay

10.21203/rs.3.rs-1133175/v1 ◽

2021 ◽

Author(s):

Jincheng Wang ◽

Juehua Yu ◽

Mengdi Wang ◽

Lingli Zhang ◽

Kan Yang ◽

...

Keyword(s):

Developmental Delay ◽

Neural Progenitor Cells ◽

De Novo ◽

Neurodevelopmental Disorder ◽

East Asian ◽

Asian Population ◽

Autism Spectrum ◽

Expression Of Genes ◽

Genome Wide ◽

Human Neural Progenitor Cells

Abstract Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder causing impairments in social communication and stereotypical behaviors, often with developmental delay or intellectual disabilities (DD/ID). Accruing evidence indicates that ASD is highly heritable and genome-wide studies on ASD cohorts have defined numerous genetic contributors. Notably, since most of these studies have been performed with individuals of European and Hispanic ancestries, thus there is a paucity of genetic analyses of ASD in the East Asian population. Here, we performed whole-exome sequencing on 772 Chinese ASD trios, combining with a previous 369 ASD trios, to identify de novo variants in 1141 ASD trios. We found that ASD without DD/ID carried less disruptive de novo variants than ASD with DD/ID. Surprisingly, we found that expression of genes with de novo variants in ASD without DD/ID were enriched in a subtype of human neural progenitor cells. Importantly, some ASD risk genes identified in this study are not present in the current ASD gene database, suggesting that there may be unique genetic contributors to ASD with the East Asian ancestry. We validated one such novel ASD candidate gene – SLC35G1 by showing that mice harboring heterozygous deletion of Slc35g1 exhibited defects in social interaction behaviors. Together, this work nominates novel ASD candidate genes and suggests that genome-wide genetic studies in ASD cohorts of different ancestries are essential to reveal the comprehensive genetic architecture of ASD.

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Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes

10.1101/2021.10.08.21264256 ◽

2021 ◽

Author(s):

Xueya Zhou ◽

Pamela Feliciano ◽

Tianyun Wang ◽

Irina Astrovskaya ◽

Chang Shu ◽

...

Keyword(s):

Genetic Risk ◽

De Novo ◽

Meta Analysis ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Loss Of Function ◽

Moderate Risk ◽

Full Spectrum ◽

Risk Genes ◽

Biological Parents

AbstractDespite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.

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Identification of Autism Risk Genes in a Chinese Cohort via Whole-Exome Sequencing with the Joint Calling Analysis

10.21203/rs.3.rs-106326/v1 ◽

2020 ◽

Author(s):

Bo Yuan ◽

Peipei Cheng ◽

Ran Zhang ◽

Yasong Du ◽

Zilong Qiu

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

East Asian ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Large Sample Size ◽

Risk Genes ◽

Genetic Components ◽

Whole Exome

Abstract Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation, transcriptional regulation, and chromatin remodeling, have been identified, the genetic analysis on east Asian ASD cohorts in the whole-geome or whole-exome level is still limited(1-5). Here we performed whole-exome sequencing on 168 ASD probands with their unaffected parents of Chinese origin. We applied a joint calling analytical pipeline based on GATK best practices and identified numerous de novo variants including single nucleotide variants (SNVs) and insertion or deletions (INDELs). By querying the Simons foundation autism research initiative (SFARI) gene database, we found that there were potential novel ASD risk genes in East Asian cohorts, which did not exist in European American populations. Furthermore, our analysis pipeline identified de novo copy number variations (CNVs) of known ASD-related gene based on a sufficiently large sample size, validated by quantitative PCR. Our work indicated that there may be differences in potential ASD genetic components existing across different geographical populations, suggesting that genomic analysis over large cohorts are required for each population in order to precisely identify ASD risk genes.

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Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

Journal of Pediatric Epilepsy ◽

10.1055/s-0041-1731816 ◽

2021 ◽

Author(s):

Evan Jiang ◽

Mark P. Fitzgerald ◽

Katherine L. Helbig ◽

Ethan M. Goldberg

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Synapse Formation ◽

De Novo ◽

Interleukin 1 ◽

Autism Spectrum ◽

Neurological Dysfunction ◽

Behavioral Disorder ◽

Clinical Genetic ◽

Severe Intellectual Disability

AbstractInterleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

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SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

10.1101/2021.01.24.427868 ◽

2021 ◽

Author(s):

Kan Yang ◽

Yuhan Shi ◽

Xiujuan Du ◽

Yuefang Zhang ◽

Shifang Shan ◽

...

Keyword(s):

Social Interaction ◽

De Novo ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Genetic Components ◽

Truncating Mutation ◽

Synaptic Functions ◽

Core Symptoms

AbstractAutism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

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EIF2AK2-related Neurodevelopmental Disorder With Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression Mimics Pelizaeus-Merzbacher Disease

Neurology Genetics ◽

10.1212/nxg.0000000000000539 ◽

2020 ◽

Vol 7 (1) ◽

pp. e539

Author(s):

Daniel G. Calame ◽

Meagan Hainlen ◽

Danielle Takacs ◽

Leah Ferrante ◽

Kayla Pence ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Copy Number Variants ◽

Retrospective Chart Review ◽

Missense Variant ◽

Chromosomal Microarray ◽

Single Nucleotide Variants ◽

Pelizaeus Merzbacher Disease ◽

Delayed Myelination

ObjectiveTo demonstrate that de novo missense single nucleotide variants (SNVs) in EIF2AK2 cause a neurodevelopmental disorder with leukoencephalopathy resembling Pelizaeus-Merzbacher disease (PMD).MethodsA retrospective chart review was performed of 2 unrelated males evaluated at a single institution with de novo EIF2AK2 SNVs identified by clinical exome sequencing (ES). Clinical and radiographic data were reviewed and summarized.ResultsBoth individuals presented in the first year of life with concern for seizures and developmental delay. Common clinical findings included horizontal and/or pendular nystagmus during infancy, axial hypotonia, appendicular hypertonia, spasticity, and episodic neurologic regression with febrile viral illnesses. MRI of the brain demonstrated severely delayed myelination in infancy. A hypomyelinating pattern was confirmed on serial imaging at age 4 years for proband 1. In proband 2, repeat imaging at age 13 months confirmed persistent delayed myelination. These clinical and radiographic features led to a strong suspicion of PMD. However, neither PLP1 copy number variants nor pathogenic SNVs were detected by chromosomal microarray and trio ES, respectively. Reanalysis of trio ES identified heterozygous de novo EIF2AK2 missense variant c.290C>T (p.Ser97Phe) in proband 1 and c.326C>T (p.Ala109Val) in proband 2.ConclusionsThe autosomal dominant EIF2AK2-related leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome should be considered in the differential diagnosis for PMD and other hypomyelinating leukodystrophies (HLDs). A characteristic history of developmental regression with febrile illnesses may help distinguish it from other HLDs.

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Linking Autism Risk Genes to Disruption of Cortical Development

Cells ◽

10.3390/cells9112500 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2500

Author(s):

Marta Garcia-Forn ◽

Andrea Boitnott ◽

Zeynep Akpinar ◽

Silvia De Rubeis

Keyword(s):

Large Scale ◽

Association Studies ◽

Neurodevelopmental Disorder ◽

Cortical Development ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Genome Wide Association Studies ◽

Restricted Interests ◽

Risk Genes ◽

Whole Exome

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development.

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