cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.15154/1238063
title: Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex families

description: NOTE: NOT ALL DATA HAS BEEN UPLOADED FOR THIS STUDY.

Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio [OR] = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts.
DOI: 10.15154/1247692
title: The contribution of mosaic variants to autism spectrum disorder

description: DOI is being issued as a reserved DOI.
DOI: 10.15154/1252218
title: De novo genic mutations among a Chinese autism spectrum disorder cohort

description: Recurrent de novo (DN) and likely gene-disruptive (LGD) mutations are important risk factors for autism spectrum disorders (ASD) but have been primarily investigated in cohorts of European ancestry. We sequenced 189 risk genes in 1,543 ASD probands (1,045 from trios) with Chinese ancestry. We report an 11-fold increase in the odds of DN LGD mutations compared to expectation under an exome-wide mutational rate model based on chimpanzee–human divergence. This enrichment for DN LGD mutations remains even after removing known syndromic ASD and intellectual disability genes from our panel (p = 1.17x10-5; odds ratio = 4.1). In aggregate, ~4% of ASD patients carry a DN mutation in one of just 29 autism risk genes. The most prevalent gene for recurrent DN mutations was SCN2A (1.1% of patients) followed by CHD8, DSCAM, MECP2, POGZ, WDFY3 and ASH1L. We identify novel DN LGD recurrences (GIGYF2, MYT1L, CUL3, DOCK8 and ZNF292) and DN mutations in genes previously implicated in ASD (ARHGAP32, NCOR1, PHIP, STXBP1, CDKL5 and SHANK1). Patient follow-up confirms phenotypic features associated with the genetic subtypes and highlights how large global cohorts might be leveraged to identify individually rare mutations in genes that together prove pathogenic significance.
DOI: 10.15154/1334287
title: Germline Mutations in Predisposition Genes in Pediatric Cancer

description: Background The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. Methods In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). Results Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer. Conclusions Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients.
DOI: 10.15154/1170505
title: Recurrent de novo mutations implicate novel genes underlying simplex autism risk.

description: Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures. These data begin to distinguish genetically distinct subtypes of autism important for aetiological classification and future therapeutics.
DOI: 10.15154/1178660
title: Decreased tryptophan metabolism in patients with Autism Spectrum Disorders

description: Background: Autism spectrum disorders (ASDs) are relatively common neurodevelopmental conditions whose
biological basis has been incompletely determined. Several biochemical markers have been associated with ASDs,
but there is still no laboratory test for these conditions.
Methods: We analyzed the metabolic profile of lymphoblastoid cell lines from 137 patients with
neurodevelopmental disorders with or without ASDs and 78 normal individuals, using Biolog Phenotype
MicroArrays.
Results: Metabolic profiling of lymphoblastoid cells revealed that the 87 patients with ASD as a clinical feature, as
compared to the 78 controls, exhibited on average reduced generation of NADH when tryptophan was the sole
energy source. The results correlated with the behavioral traits associated with either syndromal or non-syndromal
autism, independent of the genetic background of the individual. The low level of NADH generation in the
presence of tryptophan was not observed in cell lines from non-ASD patients with intellectual disability,
schizophrenia or conditions exhibiting several similarities with syndromal autism except for the behavioral traits.
Analysis of a previous small gene expression study found abnormal levels for some genes involved in tryptophan
metabolic pathways in 10 patients.
Conclusions: Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic
acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural
precursor of NAD+, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic
pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity
of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune
activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying
biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs.
Keywords: Autism, Biomarker, Tryptophan, Metabolism, Screening
DOI: 10.15154/1195995
title: RNA-Seq studies of gene expression in micro-dissected samples from the brains of individuals with autism and controls

description: We seek to understand the cellular bases of autism by using a new technology, RNA-Seq, to determine differences in gene expression in autopsy brains of subjects with well described autism versus age and sex matched neurotypical individuals. We have investigated two specific cortical areas involved in self-awareness and social reciprocity which are abnormal in autism and have found increased expression in a network of genes related to inflammation in autism group A, whereas the remaining cases, autism group B, have increased expression in a network of genes related to synapses.
DOI: 10.15154/1223860
title: The neural basis of deictic shifting in linguistic perspective-taking in high-functioning autism

description: Personal pronouns, such as 'I' and 'you', require a speaker/listener to continuously re-map their reciprocal relation to their referent, depending on who is saying the pronoun. This process, called 'deictic shifting', may underlie the incorrect production of these pronouns, or 'pronoun reversals', such as referring to oneself with the pronoun 'you', which has been reported in children with autism. The underlying neural basis of deictic shifting, however, is not understood, nor has the processing of pronouns been studied in adults with autism. The present study compared the brain activation pattern and functional connectivity (synchronization of activation across brain areas) of adults with high-functioning autism and control participants using functional magnetic resonance imaging in a linguistic perspective-taking task that required deictic shifting. The results revealed significantly diminished frontal (right anterior insula) to posterior (precuneus) functional connectivity during deictic shifting in the autism group, as well as reliably slower and less accurate behavioural responses. A comparison of two types of deictic shifting revealed that the functional connectivity between the right anterior insula and precuneus was lower in autism while answering a question that contained the pronoun 'you', querying something about the participant's view, but not when answering a query about someone else's view. In addition to the functional connectivity between the right anterior insula and precuneus being lower in autism, activation in each region was atypical, suggesting over reliance on individual regions as a potential compensation for the lower level of collaborative interregional processing. These findings indicate that deictic shifting constitutes a challenge for adults with high-functioning autism, particularly when reference to one's self is involved, and that the functional collaboration of two critical nodes, right anterior insula and precuneus, may play a critical role for deictic shifting by supporting an attention shift between oneself and others.
DOI: 10.15154/1226480
title: Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.

description: NDAR Data for this study consist of Whole Exome sequencing for the additional 56 families from SSC collection.  Other Whole Exome sequencing data and results used in this study were originally published elsewhere.  NDAR Studies 340, 320, and 317 describe the data published in Iossifov et al., 2012; Neale et al., 2012; O'Roak et al., 2012b, respectively, as cited in this publication.  The RNA-Seq data from this publication are available from NCBI at the given BioProject accession.

Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.
DOI: 10.15154/1226522
title: Maternal modifiers and parent-of-origin bias of the autism 16p11.2 CNV

description: Recurrent deletions and duplications at chromosome 16p11.2 are a major genetic contributor to autism but also associate with a wider range of pediatric diagnoses. In order to investigate the potential genetic basis for phenotype variability, we assessed the parent-of-origin of the 16p11.2 copy number variant (CNV) and the presence of additional CNVs using commercial SNP microarrays in over 100 families where detailed phenotype data were available. 
Additional phenotypic and genotypic data is available to approved researchers from the Simons Foundation SFARI Base (https://sfari.org/resources/sfari-base).
DOI: 10.15154/1226523
title: Genome sequencing of autism families reveals disruption of putative noncoding regulatory DNA

description: We performed whole-genome sequencing (WGS) of 160 genomes from 40 simplex autism families, the majority of which had no copy number variant (CNV) or candidate de novo gene-disruptive single nucleotide variant (SNV) by microarray or whole-exome sequencing (WES). SNV and CNV calling was achieved by a number of variant calling algorithms. This accession contains SNV (FreeBayes) and CNV (digital comparative genomic hybridization [dCGH], GenomeSTRiP, VariationHunter) calls from this study.
DOI: 10.15154/1240722
title: The diffusion tensor imaging (DTI) component of the NIH MRI study of normal brain development (PedsDTI)

description: The NIH MRI Study of normal brain development sought to characterize typical brain development in a population
of infants, toddlers, children and adolescents/young adults, covering the socio-economic and ethnic diversity
of the population of the United States. The study began in 1999 with data collection commencing in 2001 and
concluding in 2007. The study was designed with the final goal of providing a controlled-access database;
open to qualified researchers and clinicians,which could serve as a powerful tool for elucidating typical brain development
and identifying deviations associated with brain-based disorders and diseases, and as a resource for
developing computational methods and image processing tools.
This paper focuses on the DTI component of the NIH MRI study of normal brain development. In this work, we
describe the DTI data acquisition protocols, data processing steps, quality assessment procedures, and data
included in the database, along with database access requirements. For more details, visit http://www.
pediatricmri.nih.gov.
This longitudinal DTI dataset includes raw and processed diffusion data from 498 low resolution (3 mm) DTI
datasets from274 unique subjects, and 193 high resolution (2.5mm) DTI datasets from152 unique subjects. Subjects
range in age from10 days (from date of birth) through 22 years. Additionally, a set of age-specific DTI templates
are included. This forms one component of the larger NIHMRI study of normal brain development which
also includes T1-, T2-, proton density-weighted, and proton magnetic resonance spectroscopy (MRS) imaging
data, and demographic, clinical and behavioral data.
DOI: 10.15154/1240725
title: Analysis of the contribution of experimental bias, experimental noise, and inter-subject biological variability on the assessment of developmental trajectories in diffusion MRI studies of the brain

description: Metrics derived from the diffusion tensor, such as fractional anisotropy (FA) and mean diffusivity (MD) have
been used in many studies of postnatal brain development. A common finding of previous studies is that these
tensor-derived measures vary widely even in healthy populations. This variability can be due to inherent interindividual
biological differences as well as experimental noise. Moreover, when comparing different studies,
additional variability can be introduced by different acquisition protocols. In this study we examined scans
of 61 individuals (aged 4–22 years) from the NIH MRI study of normal brain development. Two scans were
collected with different protocols (low and high resolution). Our goal was to separate the contributions of
biological variability and experimental noise to the overall measured variance, as well as to assess potential
systematic effects related to the use of different protocols. We analyzed FA and MD in seventeen regions of
interest. We found that biological variability for both FA and MD varies widely across brain regions; biological
variability is highest for FA in the lateral part of the splenium and body of the corpus callosum along with the
cingulum and the superior longitudinal fasciculus, and for MD in the optic radiations and the lateral part of the
splenium. These regions with high inter-individual biological variability are the most likely candidates for
assessing genetic and environmental effects in the developing brain. With respect to protocol-related effects,
the lower resolution acquisition resulted in higher MD and lower FA values for the majority of regions compared
with the higher resolution protocol. However, the majority of the regions did not show any age–protocol
interaction, indicating similar trajectories were obtained irrespective of the protocol used.
DOI: 10.15154/1303416
title: Variants in adjacent oxytocin/vasopressin gene region and associations with ASD diagnosis and autism related endophenotypes

description: Background: There has been increasing interest in oxytocin (peptide: OT, gene: OXT) as a treatment pathway for neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Neurodevelopmental disorders affect functional, social, and intellectual abilities. With advances in molecular biology, research has connected multiple gene regions to the clinical presentation of ASD. Studies have also shown that the neuropeptide hormones OT and arginine vasopressin (AVP) influence mammalian social and territorial behaviors and may have treatment potential for neurodevelopmental disorders. Published data examining molecular and phenotypic variation in ASD, such as cognitive abilities, are limited. Since most studies have focused on the receptors in the OT-AVP system, we investigated genetic variation within peptide genes for association with phenotypic ASD features that help identify subgroups within the spectrum.
Methods: In this study, TDT analysis was carried out utilizing FBAT in 207 probands (156 trios) and a European Ancestry (EA) subsample (108 trios). The evolutionarily related and adjacent genes of OXT and AVP were studied for associations between the tagged single nucleotide polymorphisms and ASD diagnosis, social abilities, restrictive and repetitive behaviors, and IQ for cognitive abilities. Additionally, relationships with whole blood serotonin (WB5HT) were explored because of the developmental relationships connecting plasma levels of OT and WB5HT within ASD.
Results: Results indicate significant association between OXT rs6084258 (p=0.001) and ASD. Associations with several intermediate phenotypes were also noted: OXT rs6133010 was associated with IQ (full scale IQ, p=0.008; nonverbal IQ, p=0.009, verbal IQ, p=0.006); and OXT rs6084258 and OXT rs877172 were associated with WB5HT levels (EA, p=0.029 and p=0.050, respectively). Additionally, we measured plasma OT (pOT) levels in a subsample (N=54). Results show the same two polymorphisms, OXT rs877172 and OXT rs6084258, have significant association with pOT (EA, p=0.002 and p=0.011, respectively).
Conclusions: These findings suggest that SNPs near OXT and AVP are associated with diagnosis of ASD, social behaviors, restricted and repetitive behaviors, IQ, pOT, and WB5HT. Future studies need to replicate these findings and examine gene-interactions in other neurodevelopmental disorders. Mechanisms of action may influence early social and cognitive development that may or may not be limited to ASD diagnosis.
DOI: 10.15154/1324432
title: Frequency and Complexity of De Novo Structural Mutation in Autism

description: Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.
DOI: 10.15154/1334291
title: Preliminary findings suggest the number and volume of supragranular and infragranular pyramidal neurons are similar in the anterior superior temporal area of control subjects and subjects with autism.

description: We investigated the cytoarchitecture of the anterior superior temporal area (TA2) of the postmortem cerebral cortex in 9 subjects with autism and 9 age-matched typically developing subjects between the ages of 13 and 56 years. The superior temporal gyrus is involved in auditory processing and social cognition and its pathology has been correlated with autism. We quantified the number and soma volume of pyramidal neurons in the supragranular layers and pyramidal neurons in the infragranular layers in each subject. We did not find significant differences in the number or volume of supragranular or infragranular neurons in the cerebral cortex of subjects with autism compared to typically developing subjects. This report does not support an alteration of supragranular to infragranular neurons in autism. However, further stereological analysis of the number of cells and cell volumes in specific cortical areas is needed to better establish the cellular phenotype of the autistic cerebral cortex and to understand its clinical relevance in autism.