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PubMed2026

Elucidating the Role of SET as a Key Contributor to Neurodevelopmental Disability Within the 9q34.11 Deletion Syndrome Interval.

The 9q34.11 chromosomal region contains multiple neurodevelopmental genes involved in synaptic transmission, axonal structure and neuronal maturation. Pathogenic microdeletions, duplications and single nucleotide variants in numerous genes were previously linked with neurodevelopmental disorders (NDDs). Amongst them, SET has recently been implicated in a rare NDD with speech delay and facial dysmorphism. This study reports a female with a heterozygous de novo deletion impacting SET but not other NDD-associated genes at 9q34.11. The proband was initially diagnosed with atypical Rett syndrome with overlapping clinical features of SET haploinsufficiency. The deletion was confirmed using microarray and long-read sequencing. Subsequent quantitative proteomic evaluation identified a significant decrease of SET protein in patient-derived fibroblasts compared to control lines. This study provides insights into the proband's clinical course over their 28 year diagnostic odyssey, and emphasises the benefits of early speech therapy interventions. The proband had no functional speech, but regained the capacity to meaningfully communicate and articulate a limited vocabulary in adulthood, concordant with other reported non-paediatric cases of SET-NDD. This study expands current knowledge on the genotypic and phenotypic spectra of SET-NDD, and pinpoints a smaller 9q34.11 critical region excluding upstream NDD-associated genes, STXBP1 and SPTAN1, implicating SET as a significant NDD-associated gene.

Humans↗

PubMed2004

Interhemispheric transfer in high-functioning children and adolescents with autism spectrum disorders: a controlled pilot study.

Autism is a neurodevelopmental disorder with strong genetic influences. Clinical experience and limited empirical evidence support the view that autism may be associated with aberrant interhemispheric information transfer. This empirical controlled study examined whether, at neuropsychological testing, children with autism showed problems with interhemispheric information transfer. The study included auditory, visual, and motor measures covering information transfer within, as well as across, modalities. Thirty children (24 males, 6 females; mean age 12 years 8 months, SD 2 years 8 months; range 9 years 5 months to 17 years 5 months) without learning disability but with autism spectrum disorders were compared with 30 children from a mainstream school matched for age, sex, and IQ>75. Children with autism spectrum disorder performed significantly worse than the comparison group on most of the tests (p=0.02 for auditory perception and attention, p=0.005 for visual perception, p=0.0001 for motor control, p=0.04 for tactile perception). Results support the notion that aberrant interhemispheric transfer may be involved in the pathogenesis or clinical course of autism. The findings were not accounted for by lower IQ in the group with autism.

Adolescent↗

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↗

PubMed1994

Childhood-onset schizophrenia: an NIMH study in progress.

An ongoing study of the phenomenology, genetics, neuropsychology, physiology (eye tracking, autonomic responsivity), neuroimaging, biochemistry, and pharmacology of childhood-onset schizophrenia is described, and pilot data are presented for the first 22 subjects. Differentiation from autism "spectrum" disorders and other poorly defined, severe neurodevelopmental disorders is needed. Eye tracking and autonomic results are similar to patterns seen in later-onset schizophrenia and possibly more striking. Magnetic resonance imaging showed larger left frontal ventricular horn area for the schizophrenia subjects, larger left caudate, and lack of normal caudate asymmetry. Fluorodeoxyglucose positron emission tomography during an auditory continuous performance task revealed decreased right parietal/occipital glucose metabolic rate in the schizophrenia subjects, which may be secondary to poor attentional performance, and increased glucose metabolic rate in three left frontal regions, a left parietal region, and the right putamen. Clozapine has been effective and well tolerated in an open trial with 12 adolescents who responded poorly to typical neuroleptics; 16 subjects have been enrolled in a double-blind comparison of haloperidol and clozapine. Longitudinal study of this narrowly defined and possibly more homogeneous group of very early-onset schizophrenia subjects will be relevant to current neurodevelopmental theories addressing the role of puberty, progression of pathology, and continuity or discontinuity with later-onset schizophrenia.

Adolescent↗

PubMed2002

The epidemiology of attention-deficit/hyperactivity disorder (ADHD): a public health view.

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood. However, basic information about how the prevalence of ADHD varies by race/ethnicity, sex, age, and socio-economic status remains poorly described. One reason is that difficulties in the diagnosis of ADHD have translated into difficulties developing an adequate case definition for epidemiologic studies. Diagnosis depends heavily on parent and teacher reports; no laboratory tests reliably predict ADHD. Prevalence estimates of ADHD are sensitive to who is asked what, and how information is combined. Consequently, recent systematic reviews report ADHD prevalence estimates as wide as 2%-18%. The diagnosis of ADHD is complicated by the frequent occurrence of comorbid conditions such as learning disability, conduct disorder, and anxiety disorder. Symptoms of these conditions may also mimic ADHD. Nevertheless, we suggest that developing an adequate epidemiologic case definition based on current diagnostic criteria is possible and is a prerequisite for further developing the epidemiology of ADHD. The etiology of ADHD is not known but recent studies suggest both a strong genetic link as well as environmental factors such as history of preterm delivery and perhaps, maternal smoking during pregnancy. Children and teenagers with ADHD use health and mental health services more often than their peers and engage in more health threatening behaviors such as smoking, and alcohol and substance abuse. Better methods are needed for monitoring the prevalence and understanding the public health implications of ADHD. Stimulant medication is the treatment of choice for treating ADHD but psychosocial interventions may also be warranted if comordid disorders are present. The treatment of ADHD is controversial because of the high prevalence of medication treatment. Epidemiologic studies could clarify whether the patterns of ADHD diagnosis and treatment in community settings is appropriate. Population-based epidemiologic studies may shed important new light on how we understand ADHD, its natural history, its treatment and its consequences.

Adolescent↗

PubMedDate not supplied

Fractal dimension of cerebral cortical surface in schizophrenia and obsessive-compulsive disorder.

Schizophrenia and obsessive-compulsive disorder (OCD) are assumed to be neurodevelopmental disorders. To examine the cortical patterns in the two disorders, three-dimensional fractal dimension (FD) of skeletonized cerebral cortical surface was estimated from magnetic resonance (MR) images of 50 patients with schizophrenia, 45 patients with OCD and 26 healthy normal controls. The schizophrenic group had a significantly smaller mean FD than OCD group, and the OCD group than normal controls. The FD revealed a significant interaction effect of group-by-hemisphere, and the FD asymmetry index distinguished the schizophrenic group from normal controls. In logistic regression models, the FD and CSF volume correctly classified 95.6% of the schizophrenics from the controls and 88.0% of the patients with OCD from the controls. In the control and schizophrenic groups, the FD was not associated with any of tissue volume measures. In the OCD group, however, the FD was significantly correlated with gray matter tissue volume and intracranial volume (ICV). The results of the present study suggest that three-dimensional FD of cortical surface may be a sensitive indicator for investigation of the structural brain abnormalities in mental disorders, especially those developmentally disturbed. Further studies to explore regional FD changes in mental disorders and clinical implications of the FD including diagnostic value should be performed in the future.

Adult↗

PubMed2003

Attention-deficit hyperactivity disorder and brain-derived neurotrophic factor: a speculative hypothesis.

Brain-derived neurotrophic factor (BDNF) is important for normal neuronal development. Attention-deficit hyperactivity disorder (ADHD), a childhood-onset neurodevelopmental disorder, is characterized by inattention and hyperactivity. Psychostimulants and antidepressants are the agents commonly used for the treatment of ADHD and were also found to elevate central BDNF. It is proposed here that BDNF may play a role in the therapeutic action and pathogenesis of ADHD. This hypothesis may provide a new direction for the treatment and the pathogenesis of ADHD.

Adolescent↗

PubMed2004

Sleep disturbances in Angelman syndrome: a questionnaire study.

Only few studies are available on sleep disorders in Angelman syndrome (AS), a neurodevelopmental disorder with several behavior disturbances. The aim of this study was to determine the prevalence of sleep disorders in a relatively large group of AS subjects, compared to that of age-matched controls. Forty-nine consecutive parents of patients with AS (26 males and 23 females aged 2.3-26.2 years) were interviewed and filled out a comprehensive sleep questionnaire. Based on their genetic etiology, four groups were defined: deletion of chromosome 15q11-13 (25 subjects); methylation imprinting mutation (six subjects), UBE3A mutations (seven subjects) and paternal uniparental disomy (five subjects). In the remaining cases genetic testings were negative. A significantly high frequency of disorders of initiating and maintaining sleep, prolonged sleep latency, prolonged wakefulness after sleep onset, high number of night awakenings and reduced total sleep time were found in our AS patients, as compared to age-matched controls. We also found other types of sleep disorders, never reported before, such as enuresis, bruxism, sleep terrors, somnambulism, nocturnal hyperkinesia, and snoring. No differences were found between the four genetic aetiology groups. Moreover, we did not find important improvement of sleep disturbances from pre-pubertal to post-pubertal ages. Our data confirm the significant presence of sleep/wake rhythms fragmentation, peculiar of AS, and also demonstrate the presence of several other types of sleep disturbances in this syndrome.

Adolescent↗

PubMed2001

Lack of association of apolipoprotein E polymorphism in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) could be considered a neurodevelopmental disorder, from several lines of evidence. One of the most widely studied genes in these disorders is the apolipoprotein E gene, particularly allele 4. We analyzed for association among patients with OCD versus normal controls and cognitively impaired patients. There were no significant differences between OCD probands compared with population controls. However, the cognitively impaired group showed a higher frequency of allele apolipoprotein E gene compared with normal controls and patients with OCD.

Journal Article↗

PubMedDate not supplied

Attention deficit/hyperactivity disorder (ADHD): complex phenotype, simple genotype?

Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation and/or assortment but exhibiting a preferential familial clustering that cannot be explained by cultural or environmental causes. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and probably the most controversial. ADHD has been considered a complex genetic trait based upon the absence of a clear-cut boundary between affected and unaffected status. Furthermore, its high comorbidity with other disorders strongly suggests complex epistatic or pleiotropic effects acting in common with the environmental influences. This implies that the same gene or genes is or are associated with different and concurrently occurring phenotypes. In this study, we will review clinical and epidemiological aspects related to the ADHD phenotype, which are considered either as categorical or continuous traits. We also will discuss genetic models underlying the complexity of this behavioral phenotype and the probable role of epistatic interactions between major genes contributing to the ADHD phenotype.

Attention Deficit Disorder with Hyperactivity↗

PubMed2025

Autism spectrum disorder risk genes have convergent effects on transcription and neuronal firing patterns in primary neurons.

Autism spectrum disorder (ASD) is a highly heterogenous neurodevelopmental disorder with numerous genetic risk factors. Notably, a disproportionate number of risk genes encode transcription regulators including transcription factors and proteins that regulate chromatin. Here, we test the function of nine such ASD-linked transcription regulators by depleting them in primary cultured neurons. We then define the resulting gene expression disruptions using RNA sequencing and test effects on neuronal firing using multielectrode array recordings. We identify shared gene expression signatures across many ASD risk genes that converge on the disruption of critical synaptic genes. Fitting with this, we detect robust disruptions to neuronal firing throughout neuronal maturation. Together, these findings provide evidence that the loss of multiple ASD-linked transcriptional regulators disrupts transcription of synaptic genes and has convergent effects on neuronal firing that may contribute to enhanced ASD risk.

Autism Spectrum Disorder↗

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↗

PubMed2026

Individualized antisense oligonucleotide treatment eligibility of patients living with neurodevelopmental diseases.

With advances in genetic diagnostic tools, pathogenic variants in patients with genetic diseases are being identified at an accelerated pace. For a subset of these patients, individualized genetic interventions such as antisense oligonucleotides (ASOs) would address the disease cause. These individualized, or n-of-1, ASOs are currently being clinically applied in dozens of cases but mainly in patients with neurodegenerative diseases. For neurodevelopmental disorders, however, several questions arise: (1) Are they treatable? (2) What is the appropriate time window? (3) Does the treatment effect justify the burden and risks of treatment? In this consensus statement, we argue for the case to consider the development of individualized ASO treatment for individuals living with neurodevelopmental diseases and discuss which aspects need to be taken into consideration.

Humans↗

PubMed2025

The new frontier in understanding human and mammalian brain development.

Neurodevelopmental disorders that cause cognitive, behavioural or motor impairments affect around 15% of children and adolescents worldwide1, with diagnoses of profound autism and attention deficit hyperactivity disorder increasing in the USA and contributing to a major economic burden2,3. Yet the origins and mechanisms of these conditions remain poorly understood, limiting progress in therapies. Comprehensive cell atlases of the developing human brain, alongside those of model organisms such as mice and non-human primates, are now providing high-resolution measures of gene expression, cell-type abundance and spatial distribution. In this Perspective, we highlight recent studies that have identified novel developmental cell populations, revealed conserved and divergent patterns of cell genesis, migration and maturation across species, and begun testing hypotheses that link them to processes ranging from transcriptional control of cell fate specification to the emergence of complex behaviours. We present remaining conceptual and technical challenges and provide an outlook on how further studies of human and mammalian brain development can empower a deeper understanding of neurodevelopmental and neuropsychiatric disorders. Future efforts expanding to additional developmental stages, including adolescence, as well as whole-brain, multimodal and cross-species integration, will yield new insights into how development shapes the brain. These atlases promise to serve as essential references for unravelling mechanisms of brain function and disease vulnerability, and for advancing precision medicine.

Humans↗

PubMed1999

Familial aggregation in Rett syndrome: what is the evidence for clustering of other disorders in families of affected girls?

Rett syndrome is a neurodevelopmental disorder of unknown cause which affects girls almost exclusively. Apparently normal development in the first year of life is usually followed by loss of skills and the development of stereotypic hand movements. This study has used genetic epidemiological methods including a case control design to examine the evidence for aggregation of other disorders in families of girls with Rett syndrome. In one family there were two sisters with a condition consistent with Rett syndrome. Intellectual disability was not reported more commonly in case families (P = 0.46). However, "learning problems" were slightly commoner (P = 0.05) especially in the parental generation (P = 0.02) and these findings warrant further investigation. Mental illness and seizures were not reported at an increased prevalence. However, we would recommend the use of other strategies to collect information about psychiatric illness. Spinal curvature was reported more commonly in case families (P = 0.07) but no mechanism for clinical verification of this was included in the study. There was an apparent increase in bowel problems in the parents (P = 0.04). The major weaknesses of our study were our inability to validate any diagnosis clinically and the lack of power (due to the comparative rarity of the outcomes). The strengths are that we have been able to collect pedigree data on the families of a substantial proportion of a total population of girls with Rett syndrome and to collect comparative data from a control population. Our reported findings warrant further investigation in a larger study.

Case-Control Studies↗

PubMed2007

An investigation of the neurotrophic factor genes GDNF, NGF, and NT3 in susceptibility to ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and neurotrophic factors have been hypothesized to play a role in the pathogenesis of ADHD. Glial derived neurotrophic factor (GDNF), nerve growth factor (NGF (beta subunit)), and neurotrophic factor 3 (NT3) are members of the neurotrophin family and are involved in the survival, differentiation, and maintenance of neuronal cells. We have examined 10 coding and intronic single nucleotide polymorphisms (SNPs) across GDNF, NGF, and NT3 in a family-based association sample of 120 DSM-IV ADHD probands and their biological parents, as well as a case-control analysis with 120 sex-matched controls. Borderline significant overtransmission of the C allele of a non-synonymous C/T SNP (rs6330) in NGF which codes an alanine/valine change was found in the family-based sample (Chi-square = 3.69, odds ratio (OR) = 1.65, P = 0.05). Although this SNP is located in the 5' pro-NGF sequence and not the mature NGF protein, it may affect intracellular processing and secretion of NGF.

Adolescent↗

PubMed2006

Mouse models of autism spectrum disorders: the challenge for behavioral genetics.

Autism is a severe neurodevelopmental disorder, which typically emerges early in childhood. The core symptoms of autism include deficits in social interaction, impaired communication, and aberrant repetitive behavior, including self-injury. Despite the strong genetic component for the disease, most cases of autism have not been linked to mutations in a specific gene, and the etiology of the disorder has yet to be established. At the present time, there is no generally accepted therapeutic strategy to treat the core symptoms of autism, and there remains a critical need for appropriate animal models and relevant behavioral assays to promote the understanding and treatment of the clinical syndrome. Challenges for the development of valid mouse models include complex genetic interactions underlying the high heritability of the disease in humans, diagnosis based on deficits in social interaction and communication, and the lack of confirmatory neuropathological markers to provide validation for genetic models of the disorder. Research focusing on genes that mediate social behavior in mice may help identify neural circuitry essential for normal social interaction, and lead to novel genetic animal models of the autism behavioral phenotype.

Animals↗

PubMed2007

No evidence for preferential transmission of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor gene (BDNF) in ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable common neurodevelopmental disorder with onset in childhood. A coding SNP (rs6265, Val66Met) of the brain-derived neurotrophic factor gene (BDNF) has recently been associated with ADHD. More specifically, paternal over-transmission of the common Val66 allele to affected children had been observed. We aimed to confirm these findings in a large, sufficiently powered, and well characterized German ADHD family sample. The Val66Met polymorphism of BDNF was genotyped in 294 families comprising one or more affected sibs (468 children). Contrary to previous reports, we did not observe over-transmission of the common Val66 allele, from either parent to affected children. We did not find support for an involvement of the Val66 allele of the Val66Met polymorphism of BDNF in the pathogenesis of ADHD in our sample.

Attention Deficit Disorder with Hyperactivity↗