Enrichment of a subset of Neanderthal polymorphisms in autistic probands and siblings.

Homo sapiens and Neanderthals underwent hybridization during the Middle/Upper Paleolithic age, culminating in retention of small amounts of Neanderthal-derived DNA in the modern human genome. In the current study, we address the potential roles Neanderthal single nucleotide polymorphisms (SNP) may be playing in autism susceptibility in samples of black non-Hispanic, white Hispanic, and white non-Hispanic people using data from the Simons Foundation Powering Autism Research (SPARK), Genotype-Tissue Expression (GTEx), and 1000 Genomes (1000G) databases. We have discovered that rare variants are significantly enriched in autistic probands compared to race-matched controls. In addition, we have identified 25 rare and common SNPs that are significantly enriched in autism on different ethnic backgrounds, some of which show significant clinical associations. We have also identified other SNPs that share more specific genotype-phenotype correlations but which are not necessarily enriched in autism and yet may nevertheless play roles in comorbid phenotype expression (e.g., intellectual disability, epilepsy, and language regression). These results strongly suggest Neanderthal-derived DNA is playing a significant role in autism susceptibility across major populations in the United States.

Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series.

BACKGROUND: While an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55-200 repeats) of the FMR1 gene may be overlooked. OBJECTIVE: To report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype. METHODS: We collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS. RESULTS: Five cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity. CONCLUSION: Both hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

The Developmental Gene Hypothesis for Punctuated Equilibrium: Combined Roles of Developmental Regulatory Genes and Transposable Elements.

Theories of the genetics underlying punctuated equilibrium (PE) have been vague to date. Here the developmental gene hypothesis is proposed, which states that: 1) developmental regulatory (DevReg) genes are responsible for the orchestration of metazoan morphogenesis and their extreme conservation and mutation intolerance generates the equilibrium or stasis present throughout much of the fossil record and 2) the accumulation of regulatory elements and recombination within these same genes-often derived from transposable elements-drives punctuated bursts of morphological divergence and speciation across metazoa. This two-part hypothesis helps to explain the features that characterize PE, providing a theoretical genetic basis for the once-controversial theory. Also see the video abstract here https://youtu.be/C-fu-ks5yDs.

Ringing Decay of Gamma Oscillations and Transcranial Magnetic Stimulation Therapy in Autism Spectrum Disorder.

Research suggest that in autism spectrum disorder (ASD) a disturbance in the coordinated interactions of neurons within local networks gives rise to abnormal patterns of brainwave activity in the gamma bandwidth. Low frequency transcranial magnetic stimulation (TMS) over the dorsolateral prefrontal cortex (DLPFC) has been proven to normalize gamma oscillation abnormalities, executive functions, and repetitive behaviors in high functioning ASD individuals. In this study, gamma frequency oscillations in response to a visual classification task (Kanizsa figures) were analyzed and compared in 19 ASD (ADI-R diagnosed, 14.2 ± 3.61 years old, 5 girls) and 19 (14.8 ± 3.67 years old, 5 girls) age/gender matched neurotypical individuals. The ASD group was treated with low frequency TMS (1.0 Hz, 90% motor threshold, 18 weekly sessions) targeting the DLPFC. In autistic subjects, as compared to neurotypicals, significant differences in event-related gamma oscillations were evident in amplitude (higher) pre-TMS. In addition, recordings after TMS treatment in our autistic subjects revealed a significant reduction in the time period to reach peak amplitude and an increase in the decay phase (settling time). The use of a novel metric for gamma oscillations. i.e., envelope analysis, and measurements of its ringing decay allowed us to characterize the impedance of the originating neuronal circuit. The ringing decay or dampening of gamma oscillations is dependent on the inhibitory tone generated by networks of interneurons. The results suggest that the ringing decay of gamma oscillations may provide a biomarker reflective of the excitatory/inhibitory balance of the cortex and a putative outcome measure for interventions in autism.

Ancient roots: A Cambrian explosion of autism susceptibility genes.

Functional gene groups often share unique evolutionary patterns. The present study addresses whether autism susceptibility genes, which frequently share functional overlap, display unusual gene age and conservation patterns compared to other gene groups. Using phylostratigraphically-derived and other genetic data, the investigator explores average gene age, Ohnolog status, evolutionary rate, variation intolerance, and numbers of protein-protein (PPI) interactions across autism susceptibility, nervous system, developmental regulatory, immune, housekeeping, and luxury gene groups. Autism susceptibility genes are unusually old compared to controls, many genes having radiated in the Cambrian period in early vertebrates from whole genome duplication events. They are also tightly conserved across the animal kingdom, are highly variation intolerant, and have more PPI than other genes-all features suggesting extreme dosage sensitivity. The results of the current study indicate that autism susceptibility genes display unique radiation and conservation patterns, which may be a reflection of the major transitions in nervous system evolution that were occurring in early animals and which are still foundational in brain development today.

The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders.

Considerable interest has arisen concerning the relationship between hereditary connective tissue disorders such as the Ehlers-Danlos syndromes (EDS)/hypermobility spectrum disorders (HSD) and autism, both in terms of their comorbidity as well as co-occurrence within the same families. This paper reviews our current state of knowledge, as well as highlighting unanswered questions concerning this remarkable patient group, which we hope will attract further scientific interest in coming years. In particular, patients themselves are demanding more research into this growing area of interest, although science has been slow to answer that call. Here, we address the overlap between these two spectrum conditions, including neurobehavioral, psychiatric, and neurological commonalities, shared peripheral neuropathies and neuropathologies, and similar autonomic and immune dysregulation. Together, these data highlight the potential relatedness of these two conditions and suggest that EDS/HSD may represent a subtype of autism.

Transcranial Magnetic Stimulation in Autism Spectrum Disorders: Neuropathological Underpinnings and Clinical Correlations.

Despite growing knowledge about autism spectrum disorder (ASD), research findings have not been translated into curative treatment. At present, most therapeutic interventions provide for symptomatic treatment. Outcomes of interventions are judged by subjective endpoints (eg, behavioral assessments) which alongside the highly heterogeneous nature of ASD account for wide variability in the effectiveness of treatments. Transcranial magnetic stimulation (TMS) is one of the first treatments that targets a putative core pathologic feature of autism, specifically the cortical inhibitory imbalance that alters gamma frequency synchronization. Studies show that low frequency TMS over the dorsolateral prefrontal cortex of individuals with ASD decreases the power of gamma activity and increases the difference between gamma responses to target and nontarget stimuli. TMS improves executive function skills related to self-monitoring behaviors and the ability to apply corrective actions. These improvements manifest themselves as a reduction of stimulus bound behaviors and diminished sympathetic arousal. Results become more significant with increasing number of sessions and bear synergism when used along with neurofeedback. When applied at low frequencies in individuals with ASD, TMS appears to be safe and to improve multiple patient-oriented outcomes. Future studies should be conducted in large populations to establish predictors of outcomes (eg, genetic profiling), length of persistence of benefits, and utility of booster sessions.

Translational Neuroscience in Autism: From Neuropathology to Transcranial Magnetic Stimulation Therapies.

The presence of heterotopias, increased regional density of neurons at the gray-white matter junction, and focal cortical dysplasias all suggest an abnormality of neuronal migration in autism spectrum disorder (ASD). The abnormality is borne from a dissonance in timing between radial and tangentially migrating neuroblasts to the developing cortical plate. The uncoupling of excitatory and inhibitory cortical cells disturbs the coordinated interactions of neurons within local networks, thus providing abnormal patterns of brainwave activity in the gamma bandwidth. In ASD, gamma oscillation abnormalities and autonomic markers offer measures of therapeutic progress and help in the identification of subgroups.

Effects of Transcranial Magnetic Stimulation Therapy on Evoked and Induced Gamma Oscillations in Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a behaviorally diagnosed neurodevelopmental condition of unknown pathology. Research suggests that abnormalities of elecltroencephalogram (EEG) gamma oscillations may provide a biomarker of the condition. In this study, envelope analysis of demodulated waveforms for evoked and induced gamma oscillations in response to Kanizsa figures in an oddball task were analyzed and compared in 19 ASD and 19 age/gender-matched neurotypical children. The ASD group was treated with low frequency transcranial magnetic stimulation (TMS), (1.0 Hz, 90% motor threshold, 18 weekly sessions) targeting the dorsolateral prefrontal cortex. In ASD subjects, as compared to neurotypicals, significant differences in evoked and induced gamma oscillations were evident in higher magnitude of gamma oscillations pre-TMS, especially in response to non-target cues. Recordings post-TMS treatment in ASD revealed a significant reduction of gamma responses to task-irrelevant stimuli. Participants committed fewer errors post-TMS. Behavioral questionnaires showed a decrease in irritability, hyperactivity, and repetitive behavior scores. The use of a novel metric for gamma oscillations. i.e., envelope analysis using wavelet transformation allowed for characterization of the impedance of the originating neuronal circuit. The results suggest that gamma oscillations may provide a biomarker reflective of the excitatory/inhibitory balance of the cortex and a putative outcome measure for interventions in autism.

The modular organization of the cerebral cortex: Evolutionary significance and possible links to neurodevelopmental conditions.

The recognition of discernible anatomical regularities that appear to self-organize during development makes apparent the modular organization of the cerebral cortex. The metabolic cost engendered in sustaining interneuronal communications has emphasized the viability of short connections among neighboring neurons. This pattern of connectivity establishes a microcircuit which is repeated in parallel throughout the cerebral cortex. This canonical circuit is contained within the smallest module of information processing of the cerebral cortex; one which Vernon Mountcastle called the minicolumn. Plasticity within the brain is accounted, in part, by the presence of weak linkages that allow minicolumns to process information from a variety of sources and to quickly adapt to environmental exigencies without a need for genetic change. Recent research suggests that interlaminar correlated firing between minicolumns during the decision phase of target selection provides for the emergence of some executive functions. Bottlenecks of information processing within this modular minicolumnar organization may account for a variety of mental disorders observed in neurodevelopmental conditions.

Autism risk genes are evolutionarily ancient and maintain a unique feature landscape that echoes their function.

Previous research on autism risk (ASD), developmental regulatory (DevReg), and central nervous system (CNS) genes suggests they tend to be large in size, enriched in nested repeats, and mutation intolerant. The relevance of these genomic features is intriguing yet poorly understood. In this study, we investigated the feature landscape of these gene groups to discover structural themes useful in interpreting their function, developmental patterns, and evolutionary history. ASD, DevReg, CNS, housekeeping, and whole genome control (WGC) groups were compiled using various resources. Multiple gene features of interest were extracted from NCBI/UCSC Bioinformatics. Residual variation intolerance scores, Exome Aggregation Consortium pLI scores, and copy number variation data from Decipher were used to estimate variation intolerance. Gene age and protein-protein interactions (PPI) were estimated using Ensembl and EBI Intact databases, respectively. Compared to WGC: ASD, DevReg, and CNS genes are longer, produce larger proteins, maintain greater numbers/density of conserved noncoding elements and transposable elements, produce more transcript variants, and are comparatively variation intolerant. After controlling for gene size, mutation tolerance, and clinical association, ASD genes still retain many of these same features. In addition, we also found that ASD genes that are extremely mutation intolerant have larger PPI networks. These data support many of the recent findings within the field of autism genetics but also expand our understanding of the evolution of these broad gene groups, their potential regulatory complexity, and the extent to which they interact with the cellular network. Autism Res 2019, 12: 860-869. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism risk genes are more ancient compared to other genes in the genome. As such, they exhibit physical features related to their age, including long gene and protein size and regulatory sequences that help to control gene expression. They share many of these same features with other genes that are expressed in the brain and/or are associated with prenatal development.

Widespread Genotype-Phenotype Correlations in Intellectual Disability.

Background: Linking genotype to phenotype is a major aim of genetics research, yet the underlying biochemical mechanisms of many complex conditions continue to remain elusive. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID. Methods: Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical manifestations of complex vs. simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment patterns within subgroups. Results: Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to gene set. Conclusions: These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.

A Cohort Study Comparing Women with Autism Spectrum Disorder with and without Generalized Joint Hypermobility.

Reports suggest comorbidity between autism spectrum disorder (ASD) and the connective tissue disorder, Ehlers-Danlos syndrome (EDS). People with EDS and the broader spectrum of Generalized Joint Hypermobility (GJH) often present with immune- and endocrine-mediated conditions. Meanwhile, immune/endocrine dysregulation is a popular theme in autism research. We surveyed a group of ASD women with/without GJH to determine differences in immune/endocrine exophenotypes. ASD women 25 years or older were invited to participate in an online survey. Respondents completed a questionnaire concerning diagnoses, immune/endocrine symptom history, experiences with pain, and seizure history. ASD women with GJH (ASD/GJH) reported more immune- and endocrine-mediated conditions than their non-GJH counterparts (p = 0.001). Autoimmune conditions were especially prominent in the ASD/GJH group (p = 0.027). Presence of immune-mediated symptoms often co-occurred with one another (p < 0.001-0.020), as did endocrine-mediated symptoms (p < 0.001-0.045), irrespective of the group. Finally, the numbers of immune- and endocrine-mediated symptoms shared a strong inter-relationship (p < 0.001), suggesting potential system crosstalk. While our results cannot estimate comorbidity, they reinforce concepts of an etiological relationship between ASD and GJH. Meanwhile, women with ASD/GJH have complex immune/endocrine exophenotypes compared to their non-GJH counterparts. Further, we discuss how connective tissue regulates the immune system and how the immune/endocrine systems in turn may modulate collagen synthesis, potentially leading to higher rates of GJH in this subpopulation.

Exploratory Study of rTMS Neuromodulation Effects on Electrocortical Functional Measures of Performance in an Oddball Test and Behavioral Symptoms in Autism.

There is no accepted pathology to autism spectrum disorders (ASD) but research suggests the presence of an altered excitatory/inhibitory (E/I) bias in the cerebral cortex. Repetitive transcranial magnetic stimulation (rTMS) offers a non-invasive means of modulating the E/I cortical bias with little in terms of side effects. In this study, 124 high functioning ASD children (IQ > 80, <18 years of age) were recruited and assigned using randomization to either a waitlist group or one of three different number of weekly rTMS sessions (i.e., 6, 12, and 18). TMS consisted of trains of 1.0 Hz frequency pulses applied over the dorsolateral prefrontal cortex (DLPFC). The experimental task was a visual oddball with illusory Kanizsa figures. Behavioral response variables included reaction time and error rate along with such neurophysiological indices such as stimulus and response-locked event-related potentials (ERP). One hundred and twelve patients completed the assigned number of TMS sessions. Results showed significant changes from baseline to posttest period in the following measures: motor responses accuracy [lower percentage of committed errors, slower latency of commission errors and restored normative post-error reaction time slowing in both early and later-stage ERP indices, enhanced magnitude of error-related negativity (ERN), improved error monitoring and post-error correction functions]. In addition, screening surveys showed significant reductions in aberrant behavior ratings and in both repetitive and stereotypic behaviors. These differences increased with the total number of treatment sessions. Our results suggest that rTMS, particularly after 18 sessions, facilitates cognitive control, attention and target stimuli recognition by improving discrimination between task-relevant and task-irrelevant illusory figures in an oddball test. The noted improvement in executive functions of behavioral performance monitoring further suggests that TMS has the potential to target core features of ASD.

Atypical Processing of Novel Distracters in a Visual Oddball Task in Autism Spectrum Disorder.

Several studies have shown that children with autism spectrum disorder (ASD) show abnormalities in P3b to targets in standard oddball tasks. The present study employed a three-stimulus visual oddball task with novel distracters that analyzed event-related potentials (ERP) to both target and non-target items at frontal and parietal sites. The task tested the hypothesis that children with autism are abnormally orienting attention to distracters probably due to impaired habituation to novelty. We predicted a lower selectivity in early ERPs to target, frequent non-target, and rare distracters. We also expected delayed late ERPs in autism. The study enrolled 32 ASD and 24 typically developing (TD) children. Reaction time (RT) and accuracy were analyzed as behavioral measures, while ERPs were recorded with a dense-array EEG system. Children with ASD showed higher error rate without normative post-error RT slowing and had lower error-related negativity. Parietal P1, frontal N1, as well as P3a and P3b components were higher to novels in ASD. Augmented exogenous ERPs suggest low selectivity in pre-processing of stimuli resulting in their excessive processing at later stages. The results suggest an impaired habituation to unattended stimuli that incurs a high load at the later stages of perceptual and cognitive processing and response selection when novel distracter stimuli are differentiated from targets.

Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression.

BACKGROUND: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities. METHODS: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk. RESULTS: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS. CONCLUSIONS: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions.

Up-Regulation of Oligodendrocyte Lineage Markers in the Cerebellum of Autistic Patients: Evidence from Network Analysis of Gene Expression.

Autism is a neurodevelopmental disorder manifested by impaired social interaction, deficits in communication skills, restricted interests, and repetitive behaviors. In neurodevelopmental, neurodegenerative, and psychiatric disorders, glial cells undergo morphological, biochemical, and functional rearrangements, which are critical for neuronal development, neurotransmission, and synaptic connectivity. Cerebellar function is not limited to motor coordination but also contributes to cognition and may be affected in autism. Oligodendrocytes and specifically oligodendroglial precursors are highly susceptible to oxidative stress and excitotoxic insult. In the present study, we searched for evidence for developmental oligodendropathy in the context of autism by performing a network analysis of gene expression of cerebellar tissue. We created an in silico network model (OLIGO) showing the landscape of interactions between oligodendrocyte markers and demonstrated that more than 50 % (16 out of 30) of the genes within this model displayed significant changes of expression (corrected p value <0.05) in the cerebellum of autistic patients. In particular, we found up-regulation of OLIG2-, MBP-, OLIG1-, and MAG-specific oligodendrocyte markers. We postulate that aberrant expression of oligodendrocyte-specific genes, potentially related to changes in oligodendrogenesis, may contribute to abnormal cerebellar development, impaired myelination, and anomalous synaptic connectivity in autism spectrum disorders (ASD).