scholarly journals Contributions of Sex Chromosomes and Gonadal Hormones to the Male Bias in a Maternal Antibody-Induced Model of Autism Spectrum Disorder

2021 ◽  
Vol 12 ◽  
Author(s):  
Adriana Gata-Garcia ◽  
Amit Porat ◽  
Lior Brimberg ◽  
Bruce T. Volpe ◽  
Patricio T. Huerta ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Y Chromosome ◽  
Sex Chromosomes ◽  
Fetal Brain ◽  
Gonadal Hormones ◽  
Autism Spectrum ◽  
Maternal Antibody ◽  
Spectrum Disorder ◽  
Gonadal Hormone ◽  
Male Bias

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions that is four times more commonly diagnosed in males than females. While susceptibility genes located in the sex chromosomes have been identified in ASD, it is unclear whether they are sufficient to explain the male bias or whether gonadal hormones also play a key role. We evaluated the sex chromosomal and hormonal influences on the male bias in a murine model of ASD, in which mice are exposed in utero to a maternal antibody reactive to contactin-associated protein-like 2 (Caspr2), which was originally cloned from a mother of a child with ASD (termed C6 mice henceforth). In this model, only male mice are affected. We used the four-core-genotypes (FCG) model in which the Sry gene is deleted from the Y chromosome (Y−) and inserted into autosome 3 (TgSry). Thus, by combining the C6 and FCG models, we were able to differentiate the contributions of sex chromosomes and gonadal hormones to the development of fetal brain and adult behavioral phenotypes. We show that the presence of the Y chromosome, or lack of two X chromosomes, irrespective of gonadal sex, increased the susceptibility to C6-induced phenotypes including the abnormal growth of the developing fetal cerebral cortex, as well as a behavioral pattern of decreased open-field exploration in adult mice. Our results indicate that sex chromosomes are the main determinant of the male bias in the maternal C6-induced model of ASD. The less dominant hormonal effect may be due to modulation by sex chromosome genes of factors involved in gonadal hormone pathways in the brain.

scholarly journals Maternal iodine status in a multi-ethnic UK birth cohort: associations with autism spectrum disorder

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kirsten Jade Cromie ◽  
Diane Erin Threapleton ◽  
Charles Jonathan Peter Snart ◽  
Elizabeth Taylor ◽  
Dan Mason ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Thyroid Hormones ◽  
Iodine Deficiency ◽  
Urinary Iodine ◽  
Fetal Brain ◽  
First Trimester ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Iodine Status ◽  
Increased Risk

Abstract Background Maternal iodine requirements increase during pregnancy to supply thyroid hormones essential for fetal brain development. Maternal iodine deficiency can lead to hypothyroxinemia, a reduced fetal supply of thyroid hormones which, in the first trimester, has been linked to an increased risk of autism spectrum disorder (ASD) in the child. No study to date has explored the direct link between maternal iodine deficiency and diagnosis of ASD in offspring. Methods Urinary iodine concentrations (UIC) and iodine/creatinine ratios (I:Cr) were measured in 6955 mothers at 26–28 weeks gestation participating in the Born in Bradford (BiB) cohort. Maternal iodine status was examined in relation to the probability of a Read (CTV3) code for autism being present in a child’s primary care records through a series of logistic regression models with restricted cubic splines. Results Median (inter-quartile range) UIC was 76 μg/L (46, 120) and I:Cr was 83 μg/g (59, 121) indicating a deficient population according to WHO guidelines. Ninety two children (1·3%) in our cohort had received a diagnosis of ASD by the census date. Overall, there was no evidence to support an association between I:Cr or UIC and ASD risk in children aged 8–12 years (p = 0·3). Conclusions There was no evidence of an increased clinical ASD risk in children born to mothers with mild-to-moderate iodine deficiency at 26 weeks gestation. Alternative functional biomarkers of exposure and a wider range of conditions may provide further insight.

scholarly journals Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

2019 ◽  
Author(s):  
Charles E. Mordaunt ◽  
Julia M. Jianu ◽  
Ben Laufer ◽  
Yihui Zhu ◽  
Keith W. Dunaway ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Cord Blood ◽  
Neurodevelopmental Disorder ◽  
Familial Risk ◽  
Fetal Brain ◽  
Cell Types ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Blood Samples ◽  
Genome Bisulfite Sequencing

AbstractBackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. Since the neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development, we performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth.ResultsWe identified differentially-methylated regions (DMRs) stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development.ConclusionsAt birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD, and provides novel insights for early diagnosis and therapy.

scholarly journals Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Hyung-Goo Kim ◽  
Jill A. Rosenfeld ◽  
Daryl A. Scott ◽  
Gerard Bénédicte ◽  
Jonathan D. Labonne ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Missense Mutation ◽  
De Novo ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Craniofacial Anomalies ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Region

Abstract Background PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. Methods Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. Results We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. Conclusion Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype.

scholarly journals Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder

2016 ◽  
Author(s):  
Shan V. Andrews ◽  
Shannon E. Ellis ◽  
Kelly M. Bakulski ◽  
Brooke Sheppard ◽  
Lisa A. Croen ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Cord Blood ◽  
Peripheral Blood ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Joint Analysis ◽  
Tissue Integration ◽  
Insight Into

ABSTRACTIntegration of emerging epigenetic information with Autism Spectrum Disorder (ASD) genetic results may elucidate functional insights not possible via either type of information in isolation. We use genotype and DNA methylation (DNAm) data from cord blood and peripheral blood to identify SNPs associated with DNA methylation (meQTL lists) and additionally use publicly available fetal brain and lung meQTL lists to assess enrichment of ASD GWAS results for tissue-specific meQTLs. ASD-associated SNPs are enriched for fetal brain (OR = 3.55; p < 0.001) and peripheral blood meQTLs (OR = 1.58; p < 0.001). The CpG targets of ASD meQTLs across cord, blood, and brain tissues are enriched for immune-related pathways, consistent with other expression and DNAm results in ASD, and reveal pathways not implicated by genetic findings. This joint analysis of genotype and DNAm demonstrates the potential of both brain and blood-based DNAm for insights into ASD and psychiatric phenotypes more broadly.

Development of Neural Structure and Function in Autism Spectrum Disorder: Potential Implications for Learning Language

2020 ◽  
Vol 29 (4) ◽  
pp. 1783-1797
Author(s):  
Kelly L. Coburn ◽  
Diane L. Williams
Keyword(s):  
Autism Spectrum Disorder ◽  
Language Development ◽  
Diffusion Tensor ◽  
Autism Spectrum ◽  
Language Intervention ◽  
Spectrum Disorder ◽  
Autistic Children ◽  
Neural Structure ◽  
Complex Information ◽  
And Function

Purpose Neurodevelopmental processes that begin during gestation and continue throughout childhood typically support language development. Understanding these processes can help us to understand the disruptions to language that occur in neurodevelopmental conditions, such as autism spectrum disorder (ASD). Method For this tutorial, we conducted a focused literature review on typical postnatal brain development and structural and functional magnetic resonance imaging, diffusion tensor imaging, magnetoencephalography, and electroencephalography studies of the neurodevelopmental differences that occur in ASD. We then integrated this knowledge with the literature on evidence-based speech-language intervention practices for autistic children. Results In ASD, structural differences include altered patterns of cortical growth and myelination. Functional differences occur at all brain levels, from lateralization of cortical functions to the rhythmic activations of single neurons. Neuronal oscillations, in particular, could help explain disrupted language development by elucidating the timing differences that contribute to altered functional connectivity, complex information processing, and speech parsing. Findings related to implicit statistical learning, explicit task learning, multisensory integration, and reinforcement in ASD are also discussed. Conclusions Consideration of the neural differences in autistic children provides additional scientific support for current recommended language intervention practices. Recommendations consistent with these neurological findings include the use of short, simple utterances; repetition of syntactic structures using varied vocabulary; pause time; visual supports; and individualized sensory modifications.

Parent Education in Studies With Nonverbal and Minimally Verbal Participants With Autism Spectrum Disorder: A Systematic Review

2020 ◽  
Vol 29 (2) ◽  
pp. 890-902
Author(s):  
Lynn Kern Koegel ◽  
Katherine M. Bryan ◽  
Pumpki Lei Su ◽  
Mohini Vaidya ◽  
Stephen Camarata
Keyword(s):  
Systematic Review ◽  
Autism Spectrum Disorder ◽  
Parent Education ◽  
Autism Spectrum ◽  
Verbal Communication ◽  
Fidelity Of Implementation ◽  
Spectrum Disorder ◽  
Education Programs ◽  
Minimally Verbal ◽  
Parent Education Programs

Purpose The purpose of this systematic review was to identify parent education procedures implemented in intervention studies focused on expressive verbal communication for nonverbal (NV) or minimally verbal (MV) children with autism spectrum disorder (ASD). Parent education has been shown to be an essential component in the habilitation of individuals with ASD. Parents of individuals with ASD who are NV or MV may particularly benefit from parent education in order to provide opportunities for communication and to support their children across the life span. Method ProQuest databases were searched between the years of 1960 and 2018 to identify articles that targeted verbal communication in MV and NV individuals with ASD. A total of 1,231 were evaluated to assess whether parent education was implemented. We found 36 studies that included a parent education component. These were reviewed with regard to (a) the number of participants and participants' ages, (b) the parent education program provided, (c) the format of the parent education, (d) the duration of the parent education, (e) the measurement of parent education, and (f) the parent fidelity of implementation scores. Results The results of this analysis showed that very few studies have included a parent education component, descriptions of the parent education programs are unclear in most studies, and few studies have scored the parents' implementation of the intervention. Conclusions Currently, there is great variability in parent education programs in regard to participant age, hours provided, fidelity of implementation, format of parent education, and type of treatment used. Suggestions are made to provide both a more comprehensive description and consistent measurement of parent education programs.

The Influence of Language Context on Repetitive Speech Use in Children With Autism Spectrum Disorder

2020 ◽  
Vol 29 (1) ◽  
pp. 327-334 ◽  
Author(s):  
Allison Gladfelter ◽  
Cassidy VanZuiden
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Individual Characteristics ◽  
Receptive Vocabulary ◽  
Spectrum Disorder ◽  
School Age Children ◽  
Social Responsiveness ◽  
Contributing Factors ◽  
Children With Asd ◽  
Language Context

Purpose Although repetitive speech is a hallmark characteristic of autism spectrum disorder (ASD), the contributing factors that influence repetitive speech use remain unknown. The purpose of this exploratory study was to determine if the language context impacts the amount and type of repetitive speech produced by children with ASD. Method As part of a broader word-learning study, 11 school-age children with ASD participated in two different language contexts: storytelling and play. Previously collected language samples were transcribed and coded for four types of repetitive speech: immediate echolalia, delayed echolalia, verbal stereotypy, and vocal stereotypy. The rates and proportions of repetitive speech were compared across the two language contexts using Wilcoxon signed-ranks tests. Individual characteristics were further explored using Spearman correlations. Results The children produced lower rates of repetitive speech during the storytelling context than the play-based context. Only immediate echolalia differed between the two contexts based on rate and approached significance based on proportion, with more immediate echolalia produced in the play-based context than in the storytelling context. There were no significant correlations between repetitive speech and measures of social responsiveness, expressive or receptive vocabulary, or nonverbal intelligence. Conclusions The children with ASD produced less immediate echolalia in the storytelling context than in the play-based context. Immediate echolalia use was not related to social skills, vocabulary, or nonverbal IQ scores. These findings offer valuable insights into better understanding repetitive speech use in children with ASD.

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