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PubMed2026

Characterizing features of the genetic architecture underlying autism from a multi-ancestry perspective.

Autism spectrum disorder (ASD; MIM 209850) is reported to vary globally from 0.01% in East Asian populations to 4.36% in certain Australian cohorts. Despite high heritability estimates (61-94%), the genetic architecture underlying ASD susceptibility remains poorly characterized across diverse populations, as most genomic studies have initially focused on individuals of European ancestry. To investigate ancestry-specific genetic contributions to ASD, we analyzed whole-genome sequencing data from three independent ASD cohorts. We identified admixed ASD probands (n = 1 033) and ancestry-matched controls (n = 1 033) and performed admixture mapping (AM). AM using five continental reference populations (European, African, East Asian, South Asian, and Native American) identified five ancestry-specific ASD-susceptibility loci, including one African-related locus at 1p21.2 near S1PR1 and four Native American-associated loci at chromosome 11q13.4. Three of these latter loci were contiguous and encompassed genes previously implicated in ASD, notably SHANK2 and DHCR7, with fine-mapping identifying a significantly associated variant between the two genes (rs77695321; P = 1.52 × 10⁻⁷). The fourth Native American-associated signal at 11q13.4 overlapped the folate receptor genes FOLR1 and FOLR3, with fine-mapping identifying a genome-wide significant variant (rs7950807; P = 5.21 × 10⁻⁸). A secondary admixture mapping analysis restricted to Latin American individuals, incorporating 6 487 Brazilian controls, identified 16 additional ancestry-specific loci across seven genomic regions.

Journal Article↗

PubMed2026

A retinoic acid autoregulatory loop governing prefrontal-motor arealization.

The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behaviour, and the motor cortex (MC), which executes movement1-14. The establishment of distinct regional identities and connections along the sensorimotor-to-association axis provides a fundamental scaffold for cortical areal organization and function15-19. Retinoic acid (RA) signalling has emerged as a key regulator of PFC development19-26. However, the mechanisms that spatially confine RA signalling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we define an RA-associated gene regulatory network in the developing human PFC and identify MEIS2, which encodes a transcription factor linked to intellectual disability and autism spectrum disorder, as a key hub of this network. Conditional deletion of Meis2 in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories towards motor-like molecular and connectivity features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with Meis2 loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signalling itself, is substantially reduced in the developing medial PFC (mPFC). These findings reveal a conserved autoregulatory loop, RA → MEIS2 → ALDH1A3 → RA, that reinforces a PFC-enriched RA gradient and organizes the MC-PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signalling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to neuropsychiatric disorders.

Journal Article↗

PubMed2026

Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy.

SCN2A variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1-2% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel n = 1 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with SCN2A-related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient's phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with SCN2A-related disorder (SCN2A-RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders. ClinicalTrials.gov registration: NCT06314490 .

Adolescent↗

PubMed2026

Prenatal cell-free DNA methylome detects association with autism and maternal obesity.

Early identification of autism spectrum disorder (ASD) remains a critical challenge, particularly in utero when non-genetic factors such as maternal obesity (MO) are implicated. Here, we report results of whole-genome bisulfite sequencing of cell-free DNA (cfDNA) from third-trimester maternal plasma in a high-likelihood ASD pregnancy cohort associated with child (3 y) ASD diagnosis and/or MO. Differentially methylated regions (DMRs) between ASD and control cfDNA are strongly enriched for synaptic functions and genes previously implicated in ASD. These cfDNA ASD DMRs recapitulate those observed in ASD placenta and postmortem cortex and significantly overlap with MO DMRs. Our findings establish cfDNA methylation derived from maternal blood as a minimally invasive window into fetal brain ASD etiology, providing a framework for future mechanistic and early intervention studies. Future studies could investigate additional prenatal environmental exposures interacting with genetics during neurodevelopment.

Journal Article↗

PubMed2004

Variants of the serotonin transporter gene (SLC6A4) significantly contribute to hyperserotonemia in autism.

The role of the serotonin system in the etiology and pathogenesis of autism spectrum disorders (ASD) is not clearly defined. High levels of platelet serotonin (5-HT) have been consistently found in a proportion of patients, and it is known that specific 5-HT transporter gene (SLC6A4) variants modulate transporter reuptake function, therefore possibly influencing the occurrence of hyperserotonemia in a subset of autistic patients. We have examined the association of platelet serotonin levels with two SLC6A4 polymorphisms, 5-HTT gene-linked polymorphic region (HTTLPR) in the promoter and intron 2 variable number of tandem repeats (VNTR), in a sample of 105 ASD patients, their parents, and 52 control children. Quantitative transmission disequilibrium test (QTDT) results showed a significant effect on 5-HT levels of each SLC6A4 marker (P=0.017 for HTTLPR; P=0.047 for intron 2 VNTR) and of haplotypes of the two markers (P=0.017), with a major contribution of the L.Stin2.10 haplotype (P=0.0013). A 5-HT mean value in the range of hyperserotonemia was associated with the homozygous L.Stin2.10 haplotype (H (1,N=97)=7.76, P=0.0054), which occurred in 33% of hyperserotonemic patients against 6% of patients with normal 5-HT levels (Fisher's exact test: P=0.013, OR=8). Allele interaction at the HTTLPR locus was found, with a significant dominance variance effect on 5-HT levels. We found no transmission disequilibrium of any of the SLC6A4 variants in ASD. Our results show that the SLC6A4 gene is a significant factor in the determination of 5-HT levels, and that specific SLC6A4 variants are associated with an increased risk for hyperserotonemia in our sample of autistic patients. The biological mechanism, however, is unlikely to involve the SLC6A4 gene solely. The associated SLC6A4 alleles likely interact with other genes or environmental factors to produce the abnormally high 5-HT levels observed in this subset of autistic patients, who possibly represent a separate etiological group.

Adolescent↗

PubMed2006

Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism.

Environmental enrichment has been repeatedly shown to affect multiple aspects of brain function, and is known to improve cognitive, behavioral, and histopathological outcome after brain injuries. The purpose of the present experiments was to determine the effect of an enriched environment on behavioral aberrations observed in male rats exposed to valproic acid on day 12.5 of gestation (VPA rats), and proposed on the basis of etiological, anatomical, and behavioral data as an animal model of autism. Environmental enrichment reversed almost all behavioral alterations observed in the model. VPA rats after environmental enrichment (VPA-E) compared to VPA rats reared in standard conditions have higher sensitivity to pain and lower sensitivity to nonpainful stimuli; stronger acoustic prepulse inhibition; lower locomotor, repetitive/stereotypic-like activity, and enhanced exploratory activity; decreased anxiety; increased number of social behaviors; and shorter latency to social explorations. In comparison with control animals (Con), VPA-E rats exhibited increased number of pinnings in adolescence and social explorations in adulthood, and were less anxious in the elevated plus maze. Similar differences in social behavior and anxiety were observed between control rats exposed to environmental enrichment (Con-E) and control group reared in standard conditions. These results suggest that postnatal environmental manipulations can counteract the behavioral alterations in VPA rats. We propose environmental enrichment as an important tool for the treatment of autism spectrum disorders.

Animals↗

PubMed2001

Survey of hearing aid fitting practices for children with multiple impairments.

The fitting of amplification on young children with multiple impairments in addition to hearing loss is a challenge faced regularly by audiologists. However, very little has been published on this topic in the audiological literature. The purpose of this survey was to document hearing aid fitting practices for this population within the United States. Specifically, audiologists who regularly serve children were asked to complete a series of questions on their educational preparation and their hearing aid selection, fitting, and verification practices for children with multiple impairments. For purposes of this survey, multiple impairments included vision impairment, mental retardation, physical impairment, and autism spectrum disorders. Findings from this survey suggest that children with special needs in addition to hearing loss are typically fit in the same way and with the same type of amplification as those with hearing loss only. In addition, differences were noted in hearing aid selection, fitting, and verification practices across work settings. Future directions and research needs are suggested.

Abnormalities, Multiple↗

PubMed2006

Enhancing generalized teaching strategy use in daily routines by parents of children with autism.

PURPOSE: The purpose of this study was to examine the effects of facilitating generalized use of teaching strategies by parents of children with autism within daily routines. METHOD: Five preschool children with autism participated in intervention with a parent within daily routines in the family's home. Parents learned to include 2 teaching strategies in target routines to address their child's communication objectives. Parent-child interactions in routines were videotaped for data coding and analysis. Proactive programming of generalization occurred by systematic selection of intervention routines and by embedding intervention in multiple routines. Generalization data were collected by measuring strategy use in untrained routines. A multiple baseline design across teaching strategies was used to assess experimental effects. RESULTS: All parents demonstrated proficient use of teaching strategies and generalized their use across routines. The intervention had positive effects on child communication outcomes. All parents perceived the intervention to be beneficial. CONCLUSION: Results from this study add to the limited body of evidence supporting parent-implemented interventions in natural environments with young children with autism spectrum disorder. Additional research that replicates this approach with children of varying ages and disabilities and families with diverse characteristics is needed to support the generality of these findings.

Activities of Daily Living↗

PubMed2006

A randomized comparison of the effect of two prelinguistic communication interventions on the acquisition of spoken communication in preschoolers with ASD.

PURPOSE: This randomized group experiment compared the efficacy of 2 communication interventions (Responsive Education and Prelinguistic Milieu Teaching [RPMT] and the Picture Exchange Communication System [PECS]) on spoken communication in 36 preschoolers with autism spectrum disorders (ASD). METHOD: Each treatment was delivered to children for a maximum total of 24 hr over a 6-month period. Spoken communication was assessed in a rigorous test of generalization at pretreatment, posttreatment, and 6-month follow-up periods. RESULTS: PECS was more successful than RPMT in increasing the number of nonimitative spoken communication acts and the number of different nonimitative words used at the posttreatment period. Considering growth over all 3 measurement periods, an exploratory analysis showed that growth rate of the number of different nonimitative words was faster in the PECS group than in the RPMT group for children who began treatment with relatively high object exploration. In contrast, analogous slopes were steeper in the RPMT group than in the PECS group for children who began treatment with relatively low object exploration.

Autistic Disorder↗

PubMed2000

Intellectual disability in Western Australia.

OBJECTIVE: To investigate the prevalence of intellectual disability in Western Australia (WA), its causes, prevention, and trends over time. METHODOLOGY: Data from an administrative database of intellectual disability in WA were used to report on the trends in intellectual disability in childhood. RESULTS: The prevalence of intellectual disability was 8.3 per 1000 live births in 1980-90. For half the cases, there was no known cause for the intellectual disability. Down syndrome accounted for 14 to 15% of all cases. Since the introduction of newborn screening, no WA-born child participating in the screening program has been diagnosed with intellectual disability as a result of either phenylketonuria or congenital hypothyroidism. The rate of autism spectrum disorders rose from three to six per 10 000 in the 1980-83 WA birth cohort to 10-13 per 10 000 for the 1989-92 cohort. CONCLUSIONS: Recent linkage of this administrative database to the WA Maternal and Child Health Research Data Base provides a unique opportunity for more detailed investigation of intellectual disability and its risk factors in a large, well-ascertained population of children.

Autistic Disorder↗

PubMed2005

Social competence in children with language impairment: making connections.

Children with language problems frequently experience social difficulty. This is the case not only for children diagnosed as having impairments such as autism spectrum disorder, Asperger syndrome (AS), or mental retardation but also for children falling into diagnostic categories traditionally considered to be primarily language based (e.g., language impairment, learning disability). In considering what interventions might be most effective, it is important to consider how various aspects of development are connected. This article describes causal networks in which various factors influence the relationship between language deficits and social difficulties. Case descriptions of Joseph, an adolescent with language impairment, and Cari, a 6-year-old diagnosed with AS, illustrate the complexity of this relationship and demonstrate how intervention might be designed to facilitate positive social communication outcomes.

Affect↗

PubMed2006

Using social stories and comic strip conversations to promote socially valid outcomes for children with autism.

Very little is documented regarding the efficacy of social stories and comic strip conversations for promoting an understanding of social situations and the appropriate social behaviors of individuals with autism spectrum disorder (ASD). In addition, few studies on the efficacy of social stories have examined whether outcomes are socially valid. The purpose of this article is to respond to some of the gaps in the literature on the efficacy of a frequently used intervention for children with ASD and to describe a family-centered collaborative approach to developing social stories and comic strip conversations. The results of intervention employing an A-B design are reported for two case vignettes. Clinical implications, limitations of the available data, and potential factors contributing to outcome variability are discussed.

Autistic Disorder↗

PubMed1998

Do actions speak louder than words? The case of the disappearance of social communication oddities.

Within the last decade, researchers and clinicians have reported an increase in the incidence and diagnosis of Autism Spectrum Disorder (ASD). Various factors have been proposed for this apparent change including broader diagnostic criteria, greater public awareness, biological and environmental interactions, and earlier detection. However, it has been observed in a certain percentage of children, during the toddler and preschool years and before intervention is introduced, that severe language deficits distort social and self-regulatory behavior to such a degree that they mimic the characteristics of ASD. Professional caution is vital in this regard to describe early functioning and to defer diagnosis until the effects of intervention and treatment can be monitored over time. The case of Nicole, a preschooler with developmental delays and social communication oddities, illustrates what I believe is the most professionally responsible, cautious, family-centered, and data-based diagnostic process that links assessment, intervention, and evaluation for young children with early developmental difficulties.

Autistic Disorder↗

PubMed2005

Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism.

To study synapse formation by neuroligins, we co-cultured hippocampal neurons with COS cells expressing wild type and mutant neuroligins. The large size of COS cells makes it possible to test the effect of neuroligins presented over an extended surface area. We found that a uniform lawn of wild type neuroligins displayed on the cell surface triggers the formation of hundreds of uniformly sized, individual synaptic contacts that are labeled with neurexin antibodies. Electron microscopy revealed that these artificial synapses contain a presynaptic active zone with docked vesicles and often feature a postsynaptic density. Neuroligins 1, 2, and 3 were active in this assay. Mutations in two surface loops of neuroligin 1 abolished neuroligin binding to neurexin 1beta, a presumptive presynaptic binding partner for postsynaptic neuroligins, and blocked synapse formation. An analysis of mutant neuroligins with an amino acid substitution that corresponds to a mutation described in patients with an autistic syndrome confirmed previous reports that these mutant neuroligins have a compromised capacity to be transported to the cell surface. Nevertheless, the small percentage of mutant neuroligins that reached the cell surface still induced synapse formation. Viewed together, our data suggest that neuroligins generally promote artificial synapse formation in a manner that is associated with beta-neurexin binding and results in morphologically well differentiated synapses and that a neuroligin mutation found in autism spectrum disorders impairs cell-surface transport but does not completely abolish synapse formation activity.

Animals↗

PubMedDate not supplied

Language skills in 5-8-year-old children with 22q11 deletion syndrome.

BACKGROUND: Language impairment and delayed language onset have been described, although not investigated in detail, in children with 22q11 deletion syndrome. AIMS: To investigate different areas of language: the ability to retell a narrative, phonology, syntax and receptive vocabulary in a group of 5-8-year-old children with 22q11 deletion syndrome regardless of whether or not they had a history of speech and language difficulties. Gender differences were also investigated. METHODS & PROCEDURES: Nineteen consecutively referred children with 22q11 deletion syndrome, ten girls and nine boys, between the ages of 5 and 8 years, participated in the study. The mean full-scale IQ of the group was 78. Six children had an autism spectrum disorder, attention deficit/hyperactivity disorder, or a combination of these. Three different language tests were used: (1) the Bus Story - a test of narrative speech and language; (2) an articulation test including all Swedish phonemes in different positions; and (3) the Peabody Picture Vocabulary Test - Revised (PPVT-R). OUTCOMES & RESULTS: All but two children had an information score in the retelling task of 1 SD below the population mean. A negative correlation between age and the information score implied that the older the children, the more severe the problems. One child had an average sentence length within the normal limits and five children had subordinate clauses within normal limits. A median of 4% of the utterances included grammatical errors. About 50% of the children had a complete consonant inventory. The phonological process analysis implied delayed rather than deviant development. The group had a moderately low score for receptive vocabulary. CONCLUSIONS: Language difficulties in all investigated areas of language were found. It is suggested that speech-language impairment is a common feature of 22q11 deletion syndrome. An implication of these results is that follow-ups of language skills are important not only for pre-school children, but also for school age children and adolescents with 22q11 deletion syndrome.

Child↗

PubMed2006

Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia.

Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.

Apraxias↗

PubMed2026

UPDhmm: detecting uniparental disomy from NGS trio data.

SUMMARY: Uniparental disomies (UPDs) are copy-neutral chromosomal alterations that occur when both copies of a chromosome pair (entire or segmental) come from one parent. UPDs, including isodisomies (identical parental chromosome) and heterodisomies (two different homologs from the same parent), reflect meiotic and/or mitotic aberrations of chromosomal segregation that can be associated with congenital or acquired disease. Despite their relevance, current methods to detect UPDs using sequence data (exomes or genomes) have limited sensitivity for small events, cannot precisely determine the UPD sub-type or coordinates, and perform poorly when including individuals or populations with consanguinity. We present UPDhmm, a novel tool that uses trio-based sequence data (proband and parents) and models inheritance patterns. UPDhmm predicts the most likely inheritance scenario, normal Mendelian inheritance versus UPD event, based on genotype combinations using a Hidden Markov Model (HMM). We validated the method using simulations on exome and genome data from 1000-Genomes projects. UPDhmm overperformed currently available methods in detecting simulated UPD events in both data types. We applied UPDhmm to a collection of nearly 2400 families with a proband with autism spectrum disorder (Simons Simplex Collection Project) and identified UPD events in two affected individuals, one of them previously unreported. These two events, a paternal isodisomy of chr8 and a maternal heterodisomy of chr22, can be genetic causes of the disease, demonstrating the clinical utility of UPDhmm. Thus, UPDhmm can facilitate the incorporation of UPD detection into clinical pipelines of genomic analysis. AVAILABILITY AND IMPLEMENTATION: UPDhmm is implemented in R and is available in the Bioconductor package (version 1.5.0): https://www.bioconductor.org/packages/release/bioc/html/UPDhmm.html. The source code can be found at https://github.com/martasevilla/UPDhmm under the MIT license.

Uniparental Disomy↗

PubMed2006

Neural basis of irony comprehension in children with autism: the role of prosody and context.

While individuals with autism spectrum disorders (ASD) are typically impaired in interpreting the communicative intent of others, little is known about the neural bases of higher-level pragmatic impairments. Here, we used functional MRI (fMRI) to examine the neural circuitry underlying deficits in understanding irony in high-functioning children with ASD. Participants listened to short scenarios and decided whether the speaker was sincere or ironic. Three types of scenarios were used in which we varied the information available to guide this decision. Scenarios included (i) both knowledge of the event outcome and strong prosodic cues (sincere or sarcastic intonation), (ii) prosodic cues only or (iii) knowledge of the event outcome only. Although children with ASD performed well above chance, they were less accurate than typically developing (TD) children at interpreting the communicative intent behind a potentially ironic remark, particularly with regard to taking advantage of available contextual information. In contrast to prior research showing hypoactivation of regions involved in understanding the mental states of others, children with ASD showed significantly greater activity than TD children in the right inferior frontal gyrus (IFG) as well as in bilateral temporal regions. Increased activity in the ASD group fell within the network recruited in the TD group and may reflect more effortful processing needed to interpret the intended meaning of an utterance. These results confirm that children with ASD have difficulty interpreting the communicative intent of others and suggest that these individuals can recruit regions activated as part of the normative neural circuitry when task demands require explicit attention to socially relevant cues.

Adolescent↗