Performance Comparison of Computational Prediction Methods for the Function and Pathogenicity of Non-coding Variants

2021 ◽  
Author(s):  
Zheng Wang ◽  
Guihu Zhao ◽  
Bin Li ◽  
Zhenghuan Fang ◽  
Qian Chen ◽  
...  
Keyword(s):  
Computational Methods ◽  
Method Development ◽  
De Novo ◽  
Autism Spectrum ◽  
Common Variant ◽  
Tool Selection ◽  
Somatic Variant ◽  
Germline Variant ◽  
Regulatory Variant ◽  
Coding Variants

Non-coding variants in the human genome greatly influence some traits and complex diseases by their own regulation and modification effects. Hence, an increasing number of computational methods are developed to predict the effects of variants in the human non-coding sequences. However, it is difficult for users with insufficient knowledge about the performances of computational methods to select appropriate computational methods from dozens of methods. In order to solve this problem, we assessed 12 performance measures of 24 methods on four independent non-coding variant benchmark datasets: (Ⅰ) rare germline variant from ClinVar, (Ⅱ) rare somatic variant from COSMIC, (Ⅲ) common regulatory variant dataset, and (Ⅳ) disease associated common variant dataset. All 24 tested methods performed differently under various conditions, indicating that these methods have varying strengths and weaknesses under different scenarios. Importantly, the performance of existing methods was acceptable in the rare germline variant from ClinVar with area under curves (AUCs) of 0.4481 - 0.8033 and poor in the rare somatic variant from COSMIC (AUCs: 0.4984 - 0.7131), common regulatory variant dataset (AUCs: 0.4837 - 0.6472), and disease associated common variant dataset (AUCs: 0.4766 -0.5188). We also compared the prediction performance among 24 methods for non-coding de novo mutations in autism spectrum disorder and found that the CADD and CDTS methods showed better performance. Summarily, we assessed the performances of 24 computational methods under diverse scenarios, providing preliminary advice for proper tool selection and new method development in interpreting non-coding variants.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2020 ◽  
Author(s):  
Elliott Rees ◽  
Hugo Creeth ◽  
Hai-Gwo Hwu ◽  
Wei Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Spectrum Disorders ◽  
Coding Variants ◽  
Shared Risk

Abstract Genes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2020 ◽  
Author(s):  
Elliott Rees ◽  
Hugo D. J. Creeth ◽  
Hai-Gwo Hwu ◽  
Wei J. Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Spectrum Disorders ◽  
Coding Variants ◽  
Shared Risk

AbstractGenes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

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

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.

scholarly journals A Bibliometric Insight of Genetic Factors in ASD: Emerging Trends and New Developments

2020 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Kang Wang ◽  
Weicheng Duan ◽  
Yijie Duan ◽  
Yuxin Yu ◽  
Xiuyi Chen ◽  
...  
Keyword(s):  
Genetic Factors ◽  
De Novo ◽  
Rapid Development ◽  
The United States ◽  
Research Area ◽  
Scientific Output ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Emerging Trends ◽  
Genetic Abnormalities

Autism spectrum disorder (ASD) cases have increased rapidly in recent decades, which is associated with various genetic abnormalities. To provide a better understanding of the genetic factors in ASD, we assessed the global scientific output of the related studies. A total of 2944 studies published between 1997 and 2018 were included by systematic retrieval from the Web of Science (WoS) database, whose scientific landscapes were drawn and the tendencies and research frontiers were explored through bibliometric methods. The United States has been acting as a leading explorer of the field worldwide in recent years. The rapid development of high-throughput technologies and bioinformatics transferred the research method from the traditional classic method to a big data-based pipeline. As a consequence, the focused research area and tendency were also changed, as the contribution of de novo mutations in ASD has been a research hotspot in the past several years and probably will remain one into the near future, which is consistent with the current opinions of the major etiology of ASD. Therefore, more attention and financial support should be paid to the deciphering of the de novo mutations in ASD. Meanwhile, the effective cooperation of multi-research centers and scientists in different fields should be advocated in the next step of scientific research undertaken.

scholarly journals Targeting Poison Exons to Treat Developmental and Epileptic Encephalopathy

2021 ◽  
pp. 1-6
Author(s):  
Miriam C. Aziz ◽  
Patricia N. Schneider ◽  
Gemma L. Carvill
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Nonsense Mediated Decay ◽  
Subsequent Degradation ◽  
Alternative Splicing Events ◽  
Genetic Epilepsies

Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic <i>SCN1A</i> variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.

scholarly journals Autism Spectrum Disorder in a Girl with aDe NovoX;19 Balanced Translocation

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Marcelo Razera Baruffi ◽  
Deise Helena de Souza ◽  
Rosana Aparecida Bicudo da Silva ◽  
Ester Silveira Ramos ◽  
Danilo Moretti-Ferreira
Keyword(s):  
X Chromosome ◽  
De Novo ◽  
Recurrent Miscarriage ◽  
Chromosomal Rearrangements ◽  
Position Effect ◽  
Autism Spectrum ◽  
Balanced Translocation ◽  
Replication Banding ◽  
Conventional Cytogenetic Analysis ◽  
Gonadal Dysfunction

Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with ade novoX;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed ade novobalanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated withde novobalanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.

scholarly journals Sex-dependent role for EPHB2 in brain development and autism-associated behavior

2021 ◽  
Author(s):  
Ahlem Assali ◽  
Jennifer Y. Cho ◽  
Evgeny Tsvetkov ◽  
Abha R. Gupta ◽  
Christopher W. Cowan
Keyword(s):  
Pyramidal Neurons ◽  
De Novo ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Male Mice ◽  
Sensory Sensitivity ◽  
Hyperactivity Disorder ◽  
Specific Effects ◽  
Layer V

AbstractAutism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A de novo nonsense mutation in EPHB2 (Q857X) was discovered in a female patient with ASD [13], revealing EPHB2 as a candidate ASD risk gene. EPHB2 is a receptor tyrosine kinase implicated in axon guidance, synaptogenesis, and synaptic plasticity, positioning it as a plausible contributor to the pathophysiology of ASD and related disorders. In this study, we show that the Q857X mutation produced a truncated protein lacking forward signaling and that global disruption of one EphB2 allele (EphB2+/−) in mice produced several behavioral phenotypes reminiscent of ASD and common associated symptoms. EphB2+/− female, but not male, mice displayed increased repetitive behavior, motor hyperactivity, and learning and memory deficits, revealing sex-specific effects of EPHB2 hypofunction. Moreover, we observed a significant increase in the intrinsic excitability, but not excitatory/inhibitory ratio, of motor cortex layer V pyramidal neurons in EphB2+/− female, but not male, mice, suggesting a possible mechanism by which EPHB2 hypofunction may contribute to sex-specific motor-related phenotypes. Together, our findings suggest that EPHB2 hypofunction, particularly in females, is sufficient to produce ASD-associated behaviors and altered cortical functions in mice.

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

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.

scholarly journals CACNA1D De Novo Mutations in Autism Spectrum Disorders Activate Cav1.3 L-Type Calcium Channels

2015 ◽  
Vol 77 (9) ◽  
pp. 816-822 ◽  
Author(s):  
Alexandra Pinggera ◽  
Andreas Lieb ◽  
Bruno Benedetti ◽  
Michaela Lampert ◽  
Stefania Monteleone ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Calcium Channels ◽  
De Novo ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Spectrum Disorders

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

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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