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PubMed2025

Maternal Immune Activation Disrupts Epigenomic and Functional Maturation of Cortical Excitatory Neurons.

Elevated levels of maternal pro-inflammatory cytokines during gestation can disrupt offspring neural development, increasing the risk of neurodevelopmental disorders. We studied the effects of Poly(I:C)-induced maternal immune activation (PIC-MIA) during mid-gestation on developing cortical excitatory neurons' DNA methylation and transcriptome. PIC-MIA disrupted the developmental regulation of synapse-related genes and of genes implicated in autism spectrum disorders. Genomic regions that gain or lose DNA methylation during normal development were altered following PIC-MIA, including neurodevelopmental transcription factor binding sites. The DNA methylation and transcriptional changes were consistent with a delay in excitatory neuron maturation. Whole-cell recordings showed that PIC-MIA preferentially altered the physiological development of layer 5 excitatory neurons. Taken together, present results suggest that alterations in the epigenome, through the disruption of circuit formation, may drive the long-term consequences of maternal infection during gestation.

DNA methylation↗

PubMed2006

15q duplication associated with autism in a multiplex family with a familial cryptic translocation t(14;15)(q11.2;q13.3) detected using array-CGH.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with a strong genetic aetiology. In approximately 1% of cases, duplication of the 15q11-13 region has been reported. We report the clinical, array-comparative genomic hybridization (CGH) and cytogenetic evaluation of two individuals from a multiplex family demonstrating autism due to a maternally inherited gain of 15q11-13. Our findings indicate that unlike most 15q11-13 gains, which are caused by interstitial duplication of this region or supernumerary marker chromosomes deriving from proximal 15q, the 15q gain in this family is the result of abnormal segregation of a cryptic familial translocation with breakpoints at 14q11.2 and 15q13.3. The affected members of this family were found to have a normal karyotype at >550 band resolution. This translocation was identified using the 1-Mb resolution whole genome array (Spectral Genomics). The affected individuals have a gain of seven clones from proximal 15q, a loss of two clones from proximal 14q and a gain of two clones from 6q. Fluorescent in situ hybridization (FISH) analysis with clones from chromosomes 14 and 15, combined with DAPI reverse banding, showed an abnormal karyotype with one normal chromosome 15 and the der(15) t(14;15)(q11.2.;q13.3), resulting in the gain of proximal 15q and the loss of proximal 14q in affected individuals. The duplication of two clones from 6q in the affected subjects was also found in unaffected members of the family. Our findings suggest that the gain of 15q in autism may in some cases be due to cryptic translocations with breakpoints in the pericentromic regions of chromosome 15 and a different acrocentric chromosome. Variation in the size of pericentromic regions of any acrocentric chromosome may justify karyotype and FISH studies of autistic probands and their parents using probes from the 15q proximal region to determine recurrence risk for autism in some families.

Adolescent↗

PubMed2006

Mother-child relationship quality among adolescents and adults with autism.

The mother-child relationship in families of 202 adolescents and adults with an autism spectrum disorder living at home and its association with maternal caregiving gains and strains were examined. Findings indicate a wide range of variability in the quality of the mother-child relationship, although most were characterized as positive across multiple measures. Characteristics of the son or daughter with autism (less severe maladaptive behaviors, better health, and less social impairments) and characteristics of the mother (lower levels of pessimism) were predictive of more positive mother-child relationships. In turn, specific aspects of the mother-child relationship (greater positive affect and warmth), along with other child and maternal characteristics, predicted fewer maternal caregiving strains and, to a lesser extent, greater caregiving gains.

Adolescent↗

PubMed2005

beta2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins.

Gestational and genetic factors can contribute to autism during infancy and early childhood through their effects on fetal brain development. Previous twin studies have shown strong genetic components for the development of autism, a disorder that can have multiple causes. We investigated the effects of prenatal overstimulation of the beta2-adrenergic receptor in dizygotic twins who were exposed to terbutaline, a selective beta2-adrenergic receptor agonist used to treat premature labor, as a gestational factor. As a possible genetic mechanism, we studied two beta2-adrenergic receptor polymorphisms in twins from whom DNA was available: glycine substitution at codon 16 (16G) and glutamic acid substitution at codon 27 (27E), which show diminished desensitization in vivo compared with the wild-type receptor. Continuous terbutaline exposure for 2 weeks or longer was associated with increased concordance for autism spectrum disorders in dizygotic twins (relative risk = 2.0), with a further increase in the risk for male twins with no other affected siblings (relative risk = 4.4). A significant association was found between the presence of 16G and 27E polymorphisms in autistic patients compared with population controls (P = .006). Prenatal overstimulation of the beta2-adrenergic receptor by terbutaline or by increased signaling of genetic polymorphisms of the beta2-adrenergic receptor that have diminished desensitization can affect cellular responses and developmental programs in the fetal brain, leading to autism.

Autistic Disorder↗

PubMed2004

Early social attention impairments in autism: social orienting, joint attention, and attention to distress.

This study investigated social attention impairments in autism (social orienting, joint attention, and attention to another's distress) and their relations to language ability. Three- to four-year-old children with autism spectrum disorder (ASD; n = 72), 3- to 4-year-old developmentally delayed children (n = 34), and 12- to 46-month-old typically developing children (n = 39), matched on mental age, were compared on measures of social orienting, joint attention, and attention to another's distress. Children with autism performed significantly worse than the comparison groups in all of these domains. Combined impairments in joint attention and social orienting were found to best distinguish young children with ASD from those without ASD. Structural equation modeling indicated that joint attention was the best predictor of concurrent language ability. Social orienting and attention to distress were indirectly related to language through their relations with joint attention. These results help to clarify the nature of social attention impairments in autism, offer clues to developmental mechanisms, and suggest targets for early intervention.

Attention↗

PubMed2026

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

Humans↗

PubMed2004

Developmental, behavioural and somatic factors in pervasive developmental disorders: preliminary analysis.

OBJECTIVES: To ascertain the frequency of parental reporting of selected variables related to development, behaviour and physiology in subgroups diagnosed with pervasive developmental disorders (PDDs) and identify any significant intragroup differences. DESIGN: Retrospective cross-sectional analysis of records of patients (n = 512) held on a computerized database with a chronological age between 3 and 11 years resident in the UK/Republic of Ireland and with a formal diagnosis of autism, Asperger syndrome (AS) or autism spectrum disorder (ASD). METHODS: Non-parametric analysis (P > 0.01) of the frequency of specific variables for PDD subgroups reported by parents/primary caregiver. VARIABLES INCLUDED: timing of symptom onset, presence of skills acquired prior to symptom onset, indications of regression and regression events, current language, history of viral infections, history of ear problems, achievement of continence, current skin complaints, current bowel habits and adverse events at parturition. RESULTS: Preliminary results showed general agreement with the principle diagnostic differences between the PDD subgroups with patients diagnosed with AS showing an increased frequency of skills acquired before symptom onset (two- to three-word phrase speech, toileting skills) and a decreased frequency of regression in acquired skills when compared with other PDD subgroups. Developmental milestones such as the achievement of bowel and bladder continence were also more frequently reported for the AS group. Infantile feeding problems defined as vomiting, reflux, colic and failure to feed were more frequently reported for the AS group as was a reported history of the bacterial skin infection impetigo. Results are discussed with reference to relationships between behavioural and somatic factors in PDD.

Asperger Syndrome↗

PubMed2006

Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection.

Neuroligin abnormalities have been recently implicated in the aetiology of autism spectrum disorders (ASD), given the finding of point mutations in the two X-linked genes NLGN3 and NLGN4X and the important role of neuroligins in synaptogenesis. To enquire on the relevance and frequency of neuroligin mutations in ASD, we performed a mutation screening of NLGN3 and NLGN4X in a sample of 124 autism probands from the International Molecular Genetic Study of Autism Consortium (IMGSAC). We identified a new non-synonymous variant in NLGN3 (Thr632Ala), which is likely to be a rare polymorphism. Our data indicate that coding mutations in these genes are very rarely associated to ASD.

Autistic Disorder↗

PubMed2003

Absence of auditory 'global interference' in autism.

There has been considerable recent interest in the cognitive style of individuals with Autism Spectrum Disorder (ASD). One theory, that of weak central coherence, concerns an inability to combine stimulus details into a coherent whole. Here we test this theory in the case of sound patterns, using a new definition of the details (local structure) and the coherent whole (global structure). Thirteen individuals with a diagnosis of autism or Asperger's syndrome and 15 control participants were administered auditory tests, where they were required to match local pitch direction changes between two auditory sequences. When the other local features of the sequence pairs were altered (the actual pitches and relative time points of pitch direction change), the control participants obtained lower scores compared with when these details were left unchanged. This can be attributed to interference from the global structure, defined as the combination of the local auditory details. In contrast, the participants with ASD did not obtain lower scores in the presence of such mismatches. This was attributed to the absence of interference from an auditory coherent whole. The results are consistent with the presence of abnormal interactions between local and global auditory perception in ASD.

Acoustic Stimulation↗

PubMed2025

Distinct patterns of de novo coding variants contribute to Tourette Syndrome etiology.

Tourette syndrome (TS) is a highly heritable childhood-onset neuropsychiatric disorder characterized by persistent motor and vocal tics. While both common and rare variants contribute to TS susceptibility, the role of rare de novo mutations (DNMs) remains incompletely characterized. Here, we report findings from the largest TS whole-exome sequencing study to date, analyzing 1,466 TS trios alongside 6,714 autism spectrum disorder (ASD) trios and 5,880 unaffected sibling controls from the Simons Simplex Collection (SSC) and SPARK cohorts. Leveraging a trio-based design across these cohorts enabled calibrated assessment of DNM burden while controlling for background mutation rates. We observed a significant exome-wide enrichment of protein-truncating DNMs in TS probands, particularly within genes intolerant to loss-of-function variation (pLI ≥ 0.9), with little contribution from damaging missense variants. Notably, TS probands did not exhibit enrichment in previously implicated ASD or developmental delay (DD) genes, but elsewhere in the genome, suggesting a distinct rare variant architecture. Using a Bayesian statistical framework that integrates both de novo and rare inherited coding variants, we identified three candidate TS risk genes with FDR ≤ 0.05: PPP5C , EXOC1 , and GXYLT1 . Literature shows that they have prior links to neurodevelopmental and psychiatric disorders. These findings reveal a rare variant burden in TS that is genetically distinguishable from ASD, underscore the importance of loss-of-function mutations in TS risk, and nominate novel candidate genes for future functional investigation.

Journal Article↗

PubMed1999

Research on screening and diagnosis in autism: a work in progress.

In June 1998, the National Institutes of Health Autism Coordinating Committee (NIH/ACC) invited representatives of 13 major medical and other professional academies and associations and six national autism parent research organizations to review research data on screening and diagnosis of autism spectrum disorders. Ten review papers and more than 4,000 publications were consulted in this effort. This paper highlights some promising areas for research identified in this process. One of the highest priorities is the search for the ultimate diagnostic indicator, a biological marker(s), for example, genetic, metabolic, immunologic, neurologic, that will distinguish autism unequivocally from other developmental disabilities. In the interim, research on infant screening and diagnosis might lower the threshold age for diagnosis to 8-12 months. The role of sensory-motor disorders in early diagnosis needs further research. Earlier and better diagnosis of co-occurring, potentially treatable disorders, including epileptic and epileptiform disorders, has implications both for diagnosis and treatment. Pharmacogenetic and pharmacogenomic research strategies could help diagnose subtypes and responders versus nonresponders to potential treatments. Better endpoints and outcome measures are needed, including improved procedures for cognitive and neuropsychological testing, more knowledge about verbal and nonverbal communication milestones, and less invasive and more sensitive neuroimaging measures. Critical questions remain regarding regression after apparently normal development, and about possible environmental precipitants. Finally, field trials of the reliability and validity of screening and diagnosis using the newly developed practice guidelines are needed.

Autistic Disorder↗

PubMed2005

Resting cortical brain activity and social behavior in higher functioning children with autism.

BACKGROUND: Psychophysiological measurement of processes related to social behavior may be valuable for research on individual differences and subgroups among children with autism spectrum disorders (Coleman, 1987; Dawson, Klinger, Panagiotides, Lewy, & Castelloe, 1995; Modahl et al., 1998). In particular, recent research and theory suggests that measures of resting anterior EEG asymmetry reflect complex brain processes associated with individual differences in approach or avoidance motivation that may be associated with social and emotional interaction tendencies among children with autism. METHOD: This hypothesis was examined in a study of the relations among resting anterior asymmetry, social impairment, and social anxiety in 23 high functioning children with autism (HFA) and 20 controls (age range 9-14 years). RESULTS: These groups were significantly different on the measures of anterior asymmetry, social symptoms and anxiety-related measures. Moreover, HFA children who displayed right frontal asymmetry (RFA group) displayed more symptoms of social impairments and better visual analytic skills than did children who displayed left frontal asymmetry (LFA group). Alternatively, while the LFA group displayed fewer symptoms of social impairment they also reported greater levels of social anxiety, social stress, and lower satisfaction with interpersonal relations than did the RFA group. CONCLUSIONS: These observations indicate that anterior EEG asymmetry may be a marker of motivation and emotion processes that refract the autism taxon into important individual differences in social presentation among higher functioning children.

Adolescent↗

PubMed2003

Deficits in reciprocal social behavior in male twins: evidence for a genetically independent domain of psychopathology.

OBJECTIVE: Previous studies have demonstrated substantial genetic influences on many child psychiatric disorders, including autism. In this study the authors attempted to quantify the degree to which genetic influences on deficits in reciprocal social behavior (a defining feature of pervasive developmental disorders) are shared with genetic influences on other domains of behavior in children. METHOD: Child Behavior Checklists (CBCL) and Social Responsiveness Scales (SRS) were completed for an epidemiological sample of 219 pairs of male twins. The SRS (formerly known as the Social Reciprocity Scale) is a measure of social impairment that distinguishes children with autism spectrum disorders from those with other child psychiatric disorders. RESULTS: Regression analysis indicated that CBCL syndromes account for 43% of the variance in SRS scores. Bivariate analyses revealed that SRS scores are affected, in part, by phenotypic influences from the CBCL Social Problem syndrome. Forty-four percent of the causal influences on SRS scores, however, are independent from those on CBCL syndromes and are genetic in nature (90% confidence interval: 0.38-0.49). CONCLUSION: These results support the existence of a continuous distribution of deficits in reciprocal social behavior in the population, which are substantially genetically independent from other domains of child psychopathology.

Adolescent↗

PubMed2006

Amygdala volume and nonverbal social impairment in adolescent and adult males with autism.

BACKGROUND: Autism is a syndrome of unknown cause, marked by abnormal development of social behavior. Attempts to link pathological features of the amygdala, which plays a key role in emotional processing, to autism have shown little consensus. OBJECTIVE: To evaluate amygdala volume in individuals with autism spectrum disorders and its relationship to laboratory measures of social behavior to examine whether variations in amygdala structure relate to symptom severity. DESIGN: We conducted 2 cross-sectional studies of amygdala volume, measured blind to diagnosis on high-resolution, anatomical magnetic resonance images. Participants were 54 males aged 8 to 25 years, including 23 with autism and 5 with Asperger syndrome or pervasive developmental disorder not otherwise specified, recruited and evaluated at an academic center for developmental disabilities and 26 age- and sex-matched community volunteers. The Autism Diagnostic Interview-Revised was used to confirm diagnoses and to validate relationships with laboratory measures of social function. MAIN OUTCOME MEASURES: Amygdala volume, judgment of facial expressions, and eye tracking. RESULTS: In study 1, individuals with autism who had small amygdalae were slowest to distinguish emotional from neutral expressions (P=.02) and showed least fixation of eye regions (P=.04). These same individuals were most socially impaired in early childhood, as reported on the Autism Diagnostic Interview-Revised (P<.04). Study 2 showed smaller amygdalae in individuals with autism than in control subjects (P=.03) and group differences in the relation between amygdala volume and age. Study 2 also replicated findings of more gaze avoidance and childhood impairment in participants with autism with the smallest amygdalae. Across the combined sample, severity of social deficits interacted with age to predict different patterns of amygdala development in autism (P=.047). CONCLUSIONS: These findings best support a model of amygdala hyperactivity that could explain most volumetric findings in autism. Further psychophysiological and histopathological studies are indicated to confirm these findings.

Adolescent↗

PubMed2026

De novo variants in the poly(rC)-binding protein gene PCBP1 cause a neurodevelopmental disorder.

Poly(rC)-binding protein 1 (PCBP1), a splicing factor and key member of the hnRNP E family, was initially characterized for its tumor suppressive properties. More recently, its role in gene regulation in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 16 de novo pathogenic variants in PCBP1 across 17 subjects from 16 unrelated families. All affected individuals exhibited intellectual disability (ID), with autism spectrum disorder (ASD) as a prominent feature. Functional analysis in primary hippocampal mouse neuron cultures indicated that PCBP1 variants impair dendritic arborization, underscoring their deleterious effects. Transcriptomic profiling by RNA sequencing of subject-derived T cells showed a distinctive signature characterized by significantly increased exon skipping. These results highlight the contribution of PCBP1 in neurogenesis and neuritogenesis, which is impacted by loss-of-function variants expressed in neuronal cells, thereby supporting the link between splicing defects and neurodevelopmental disorders. Collectively, our findings demonstrate the prominent role of PCBP1 in neurodevelopment, reaffirming the importance of splicing regulation in mammalian neurodevelopment.

Journal Article↗

PubMed2002

Autism and the X chromosome: no linkage to microsatellite loci detected using the affected sibling pair method.

The etiology of autism spectrum disorders (ASDs) is poorly understood, although it is clear that genetic factors play a major role. ASDs appear to be a heterogeneous group of disorders, making genetic analysis difficult in the absence of etiologically definable subgroups. The excess of males in the affected population has led to suggestions that an X-linked locus could play a role in the causation of autism or a related pervasive developmental disorder. To examine this, we have investigated the genotypes of 31 families with two or more affected boys, at a series of 16 highly polymorphic loci distributed along the X chromosome with an average interlocus distance of 12 cM, in order to identify regions of significantly increased concordance among pairs of affected brothers. No locus tested showed a significant increase in concordance, supporting findings by others that there are no genes of major effect located on the X chromosome that contribute to increased susceptibility to ASD.

Alleles↗

PubMed2005

Health issues and quality of life in women with intellectual disability.

BACKGROUND: Although there is anecdotal evidence of an increase in both period pain and premenstrual syndrome (PMS) in women with intellectual disabilities (ID), there are only brief mentions of it in the literature. METHOD: Questionnaires were distributed to parents of women with Down syndrome (DS) or Autism Spectrum Disorder (ASD), resulting in 24 respondents from Australia and New Zealand. The purpose of the study was to ascertain how period pain and PMS presents in women with ID. RESULTS: Results were analyzed by disability group, and communication ability. Women with DS were more often able to state that they had pain, or point to the location of the pain than women with either autism or Asperger Syndrome (AS). Additionally, women with DS or ASD appeared to have a higher rate of period pain than women in the general population, but the presence of pain more often had to be deduced from behavioural changes. CONCLUSION: Further research with a larger number of women with disability, and across a wider range of disabilities is required to determine generalizability of these findings.

Adolescent↗

PubMed2005

Use of the questionnaire on resources and stress (QRS-F) with parents of young children with autism.

The Questionnaire on Resources and Stress (Friedrich, short form: QRS-F) has been used widely with parents of children with disabilities. However, its psychometric properties in parents of young children with autism have not been established. Here, 174 mothers and 43 fathers of children under 6 years with autism spectrum disorder were studied by two independent research teams. Each parent completed a 31-item version of the QRS-F. Factor analysis of the mothers' scores on these items failed to identify an expected two- or three-factor structure. Thus, the properties of a total stress score were explored. Analyses revealed evidence of good reliability, and expected associations with social support, coping and autism severity. These analyses lend preliminary support to the convergent validity of the scale. Overall, the data support the use of a total stress score from the 31-item version of the QRS-F in research with parents of young children with autism.

Adaptation, Psychological↗