scholarly journals Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

2021 ◽  
Author(s):  
Ricardo Harripaul ◽  
Ansa Rabia ◽  
Nasim Vasli ◽  
Anna Mikhailov ◽  
Ashlyn Rodrigues ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
De Novo ◽  
Splice Variants ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Loss Of Function ◽  
Candidate Sequence

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that affects about 1 in 55 children worldwide and imposes enormous economic and socioemotional burden on families and communities. Genetic studies of ASD have identified de novo copy number variants (CNVs) and point mutations that contribute significantly to the genetic architecture of ASD, but the majority of these studies were conducted in outbred populations, which are not ideal for detecting autosomal recessive (AR) inheritance. However, several studies have investigated ASD genetics in consanguineous populations and point towards AR as an under-appreciated source of ASD variants. Here, we used trio whole exome sequencing (WES) to look for rare variants for ASD in 115 proband-mother-father trios from populations with high rates of consanguinity, namely Pakistan, Iran, and Saudi Arabia. In total, we report 87 candidate sequence variants, with 57% biallelic, 21% autosomal dominant/de novo, and the rest X-linked. 52% of the variants were loss of function (LoF) or putative LoF (splice site, stop loss) and 47% non-synonymous. Our analysis indicates an enrichment of previously identified and candidate AR genes. These include variants in genes previously reported for AR ASD and/or intellectual disability (ID), such as AGA, ASL, ASPA, BTN3A2, CC2D1A, DEAF1, HTRA2, KIF16B, LINS1, MADD, MED25, MTHFR, RSRC1, TECPR2, VPS13B, ZNF335, and 32 previously unreported candidates, including 15 LoF or splice variants, in genes such as DAGLA, EFCAB8, ENPP6, FAXDC2, ILDR2, PKD1L1, SCN10A, and SLC36A1. We also identified candidate biallelic exonic loss CNVs a number of trios, implicating genes including DNAH7, and DHRS4/DHRS4L2.

scholarly journals Genetic contributions to autism spectrum disorder

2021 ◽  
pp. 1-14
Author(s):  
A. Havdahl ◽  
M. Niarchou ◽  
A. Starnawska ◽  
M. Uddin ◽  
C. van der Merwe ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
De Novo ◽  
Point Mutations ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Individual Risk ◽  
Future Research ◽  
Risk Genes

Abstract Autism spectrum disorder (autism) is a heterogeneous group of neurodevelopmental conditions characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests. This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings. The clinical heterogeneity of autism is mirrored by a complex genetic architecture involving several types of common and rare variants, ranging from point mutations to large copy number variants, and either inherited or spontaneous (de novo). More than 100 risk genes have been implicated by rare, often de novo, potentially damaging mutations in highly constrained genes. These account for substantial individual risk but a small proportion of the population risk. In contrast, most of the genetic risk is attributable to common inherited variants acting en masse, each individually with small effects. Studies have identified a handful of robustly associated common variants. Different risk genes converge on the same mechanisms, such as gene regulation and synaptic connectivity. These mechanisms are also implicated by genes that are epigenetically and transcriptionally dysregulated in autism. Major challenges to understanding the biological mechanisms include substantial phenotypic heterogeneity, large locus heterogeneity, variable penetrance, and widespread pleiotropy. Considerable increases in sample sizes are needed to better understand the hundreds or thousands of common and rare genetic variants involved. Future research should integrate common and rare variant research, multi-omics data including genomics, epigenomics, and transcriptomics, and refined phenotype assessment with multidimensional and longitudinal measures.

scholarly journals An Overview of Genetic and Environmental Risk of Autism Spectrum Disorder

2019 ◽  
pp. 37-44 ◽  
Author(s):  
Jianjun Ou ◽  
Ruiting Liu ◽  
Yidong Shen ◽  
Kun Xia ◽  
Jingping Zhao
Keyword(s):  
Autism Spectrum Disorder ◽  
Environmental Factors ◽  
Rare Variants ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Spectrum Disorder ◽  
Nucleotide Polymorphisms ◽  
Genetic And Environmental Factors

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder typically diagnosed in children in the first few years of life. Genetic studies have demonstrated a moderate to high heritability of ASD, but only a limited number of single nucleotide polymorphisms (SNPs) have been identified. Meanwhile, numerous single de novo rare variants and copy number variations have been detected in patients with ASD, which are likely caused by environmental factors. Here we provide an overview of genetic and environmental factors that may contribute to the risk of ASD and we recommend that further study should be focused on both genes and environmental factors, as well as their interactions with the expectation that epigenetic studies will lead to understanding the link between the environment and risk of ASD.

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 Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1053
Author(s):  
Jasleen Dhaliwal ◽  
Ying Qiao ◽  
Kristina Calli ◽  
Sally Martell ◽  
Simone Race ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Compound Heterozygous ◽  
Variable Effect ◽  
Gabaergic Neurotransmission ◽  
High Heritability ◽  
Compound Heterozygous Variants

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

25. Identification of De novo, Deleterious Mutations through Exome Sequencing of Sporadic Autism Spectrum Disorder Trios

2018 ◽  
Author(s):  
Shalandra Wood
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
De Novo Mutations ◽  
Genetic Etiology ◽  
Affected Child ◽  
Biological Relevance

  Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder that has a strong genetic component consisting of many genes contributing to its cause. To help understand this complex genetic etiology, we are looking for novel genes that may be involved in the reason individuals develop ASD. We are doing this by using 5 sporadic ASD cases to determine de novo mutations (mutations new to the affected child that are not previously found in the family). These sporadic cases ensure that the disorder is not likely to arise through any inherited mutations, but through a new mutation found solely in the affected child. We use a trio analysis in which the genes of the affected child are compared to those of their mother and father, so pure de novo single nucleotide polymorphisms (SNPs) can be determined. These SNPs are then filtered based on predicted deleterious effect, quality and biological relevance. Using whole-exome sequencing on these 5 sporadic trios numerous deleterious, de novo mutations have been determined. These are being reviewed for biological relevance, and will be validated using Sanger Sequencing. Of these proposed SNPs being validated a few, such as SHANK3 and DVL1, have previously been linked to ASD. Whereas others, such as C11orf31, are novel candidate genes for the disorder. Through this experiment our understanding of the genetic etiology of ASD continues to grow and evolve, leading to greater insight into this disorder and new directions for possible treatments

scholarly journals Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

2021 ◽  
Author(s):  
Felix Marbach ◽  
◽  
Georgi Stoyanov ◽  
Florian Erger ◽  
Constantine A. Stratakis ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Global Developmental Delay ◽  
Missense Variants ◽  
Large Patient ◽  
Significant Enrichment

Abstract Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

scholarly journals The female protective effect against autism spectrum disorder

2021 ◽  
Author(s):  
Emilie M. Wigdor ◽  
Daniel J. Weiner ◽  
Jakob Grove ◽  
Jack M. Fu ◽  
Wesley K. Thompson ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Protective Effect ◽  
Rare Variants ◽  
De Novo ◽  
Autism Spectrum ◽  
High Impact ◽  
Spectrum Disorder ◽  
Polygenic Risk ◽  
Female Protective Effect ◽  
Nationally Representative

Autism spectrum disorder (ASD) is diagnosed 3-4 times more frequently in males than in females. Genetic studies of rare variants support a female protective effect (FPE) against ASD. However, sex differences in common, inherited genetic risk for ASD are less studied. Leveraging the nationally representative Danish iPSYCH resource, we found siblings of female ASD cases had higher rates of ASD than siblings of male ASD cases (P < 0.01). In the Simons Simplex and SPARK collections, mothers of ASD cases carried more polygenic risk for ASD than fathers of ASD cases (P = 7.0 ⨉ 10-7). Male unaffected siblings under-inherited polygenic risk (P = 0.03); female unaffected siblings did not. Further, female ASD cases without a high-impact de novo variant over-inherited nearly three-fold the polygenic risk of male cases with a high-impact de novo (P = 0.02). Our findings support a FPE against ASD that includes common, inherited genetic variation.

scholarly journals Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

2020 ◽  
Author(s):  
Felix Marbach ◽  
Georgi Stoyanov ◽  
Florian Erger ◽  
Jill A. Rosenfeld ◽  
Erin Torti ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
In Vivo Studies ◽  
Global Developmental Delay ◽  
Missense Variants ◽  
Significant Enrichment

Purpose: We characterize the phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder, who carry heterozygous missense-variants of the PRKAR1B gene. Methods: Variants of PRKAR1B were identified by single-exome or trio-exome analysis. We contacted the families and physicians of the six individuals in order to collect clinical and phenotypic information. Results: PRKAR1B encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA), and is predominantly expressed in the central nervous system. Recent studies of patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B, and in vivo studies of the murine ortholog demonstrated altered hippocampal function and reduced neurogenic inflammation and long-term nociceptive pain in R1β-deficient mice. In our study, de novo origin of the PRKAR1B-variants could be confirmed in five out of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p. Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia has been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. Conclusion: Our study provides strong evidence for a novel, PRKAR1B-related neurodevelopmental disorder.

scholarly journals Whole-genome analysis of de novo and polymorphic retrotransposon insertions in Autism Spectrum Disorder

2021 ◽  
Author(s):  
Rebeca Borges-Monroy ◽  
Chong Chu ◽  
Caroline Dias ◽  
Jaejoon Choi ◽  
Soohyun Lee ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Mendelian Disease ◽  
Whole Genome ◽  
Loss Of Function ◽  
Whole Genome Analysis ◽  
Bioinformatic Tools

AbstractRetrotransposons are dynamic forces in evolutionary genomics and have been implicated as causes of Mendelian disease and hereditary cancer, but their role in Autism Spectrum Disorder (ASD) has never been systematically defined. Here, we report 86,154 polymorphic retrotransposon insertions including >60% not previously reported and 158 de novo retrotransposition events identified in whole genome sequencing (WGS) data of 2,288 families with ASD from the Simons Simplex Collection (SSC). As expected, the overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 104, and 192 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 20 births total, while the location of transposon insertions differed between ASD and unaffected individuals. ASD cases showed more de novo L1 insertions than expected in ASD genes, and we also found de novo intronic retrotransposition events in known syndromic ASD genes in affected individuals but not in controls. Additionally, we observed exonic insertions in genes with a high probability of being loss-of-function intolerant, including a likely causative exonic insertion in CSDE1, only in ASD individuals. Although de novo retrotransposition occurs less frequently than single nucleotide and copy number variants, these findings suggest a modest, but important, impact of intronic and exonic retrotransposition mutations in ASD and highlight the utility of developing specific bioinformatic tools for high-throughput detection of transposable element insertions.

scholarly journals Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder

Mobile DNA ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rebeca Borges-Monroy ◽  
Chong Chu ◽  
Caroline Dias ◽  
Jaejoon Choi ◽  
Soohyun Lee ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Mendelian Disease ◽  
Whole Genome ◽  
Loss Of Function ◽  
Whole Genome Analysis ◽  
Bioinformatic Tools ◽  
High Throughput Detection

Abstract Background Retrotransposons have been implicated as causes of Mendelian disease, but their role in autism spectrum disorder (ASD) has not been systematically defined, because they are only called with adequate sensitivity from whole genome sequencing (WGS) data and a large enough cohort for this analysis has only recently become available. Results We analyzed WGS data from a cohort of 2288 ASD families from the Simons Simplex Collection by establishing a scalable computational pipeline for retrotransposon insertion detection. We report 86,154 polymorphic retrotransposon insertions—including > 60% not previously reported—and 158 de novo retrotransposition events. The overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 117, and 206 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 21 births total. However, ASD cases showed more de novo L1 insertions than expected in ASD genes. Additionally, we observed exonic insertions in loss-of-function intolerant genes, including a likely pathogenic exonic insertion in CSDE1, only in ASD individuals. Conclusions These findings suggest a modest, but important, impact of intronic and exonic retrotransposon insertions in ASD, show the importance of WGS for their analysis, and highlight the utility of specific bioinformatic tools for high-throughput detection of retrotransposon insertions.

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