A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disease (~0.9) with a complex genetic etiology. It is initially characterized by altered cognitive ability which commonly includes impaired language and communication skills as well as fundamental deficits in social interaction. Despite the large amount of studies described so far, the high clinical diversity affecting the autism phenotype remains poorly explained. Recent studies suggest that rare genomic variations, in particular copy number variation (CNV), may account for a significant proportion of the genetic basis of ASD. The use of disease-discordant monozygotic twins represents a powerful strategy to identifyde novoand inherited CNV in the disorder. Here we present the results of a comparative genome hybridization (CGH) analysis with a pair of monozygotic twins affected of ASD with significant differences in their clinical manifestations that specially affect speech language impairment and communication skills. Array CGH was performed in three different tissues: blood, saliva, and hair follicle, in an attempt to identify germinal and somatic CNV regions that may explain these differences. Our results argue against a role of large CNV rearrangements as a molecular etiology of the observed differences. This forwards future research to explorede novopoint mutation and epigenomic alterations as potential explanations of the observed clinical differences.

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A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

npj Genomic Medicine ◽

10.1038/s41525-021-00254-0 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Livia O. Loureiro ◽

Jennifer L. Howe ◽

Miriam S. Reuter ◽

Alana Iaboni ◽

Kristina Calli ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number ◽

De Novo ◽

Sequence Data ◽

Copy Number Variants ◽

Somatic Mosaicism ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Variable Expression ◽

Genomic Location

AbstractAutism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.

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Psychotic symptoms in 16p11.2 copy number variant carriers

10.1101/621250 ◽

2019 ◽

Author(s):

Amandeep Jutla ◽

J. Blake Turner ◽

LeeAnne Green Snyder ◽

Wendy K. Chung ◽

Jeremy Veenstra-VanderWeele

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number ◽

Copy Number Variant ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Psychotic Symptoms ◽

Obsessive Compulsive ◽

Logistic Regression Models ◽

Compulsive Disorder ◽

Using Data

Abstract16p11.2 copy number variation (CNV) is implicated in neurodevelopmental disorders, with the duplication and deletion associated with autism spectrum disorder (ASD) and the duplication associated with schizophrenia (SCZ). The 16p11.2 CNV may therefore provide insight into the relationship between ASD and SCZ, distinct disorders that co-occur at an elevated rate and are difficult to distinguish from each other and from common co-occurring diagnoses such as obsessive compulsive disorder (OCD), itself a potential risk factor for SCZ. As psychotic symptoms are core to SCZ but distinct from ASD, we sought to examine their predictors in a population (n = 546) of 16p11.2 CNV carriers and their noncarrier siblings recruited by the Simons Variation in Individuals Project. We hypothesized that psychotic symptoms would be most common in duplication carriers followed by deletion carriers and noncarriers, that an ASD diagnosis would predict psychotic symptoms among CNV carriers, and that OCD symptoms would predict psychotic symptoms among all participants. Using data collected across multiple measures, we identified 19 participants with psychotic symptoms. Logistic regression models adjusting for biological sex, age, and IQ found that 16p11.2 duplication and ASD diagnosis predicted psychotic symptom presence. Our findings suggest that the association between 16p11.2 duplication and psychotic symptoms is independent of ASD diagnosis and that ASD diagnosis and psychotic symptoms may be associated in 16p11.2 CNV carriers.Lay SummaryEither deletion or duplication at chromosome 16p11.2 raises the risk of autism spectrum disorder, and duplication, but not deletion, has been reported in schizophrenia. In a sample of 16p11.2 deletion and duplication carriers, we found that having the duplication or having an autism diagnosis may increase the risk of psychosis, a key feature of schizophrenia.

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Faculty Opinions recommendation of Absence of substantial copy number differences in a pair of monozygotic twins discordant for features of autism spectrum disorder.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718287179.793491409 ◽

2014 ◽

Author(s):

Isaac Kohane

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number ◽

Monozygotic Twins ◽

Autism Spectrum ◽

Spectrum Disorder

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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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Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder

Frontiers in Genetics ◽

10.3389/fgene.2018.00665 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 2

Author(s):

Yanjie Fan ◽

Xiujuan Du ◽

Xin Liu ◽

Lili Wang ◽

Fei Li ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Copy Number ◽

Autism Spectrum ◽

Copy Number Variations ◽

Spectrum Disorder ◽

Chinese Cohort

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Increased burden of deleterious variants in essential genes in autism spectrum disorder

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613195113 ◽

2016 ◽

Vol 113 (52) ◽

pp. 15054-15059 ◽

Cited By ~ 30

Author(s):

Xiao Ji ◽

Rachel L. Kember ◽

Christopher D. Brown ◽

Maja Bućan

Keyword(s):

Autism Spectrum Disorder ◽

Large Scale ◽

De Novo ◽

Autism Spectrum ◽

Essential Genes ◽

Spectrum Disorder ◽

Model Organisms ◽

Disease Genes ◽

Priority List ◽

Human Orthologs

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.

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