Publications by authors named "Edwin H Cook"

192 Publications

Case Report: Association of Comorbid Psychiatric Disorders and Sigmoid Prolapse with de novo POGZ Mutation.

J Autism Dev Disord 2021 Apr 28. Epub 2021 Apr 28.

Department of Psychiatry, Institute for Juvenile Research, University of Illinois College of Medicine at Chicago, 1747 W. Roosevelt Road, Suite 155, Chicago, IL, 60608, USA.

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http://dx.doi.org/10.1007/s10803-021-05032-6DOI Listing
April 2021

Elevated Polygenic Burden for Autism Spectrum Disorder Is Associated With the Broad Autism Phenotype in Mothers of Individuals With Autism Spectrum Disorder.

Biol Psychiatry 2021 03 12;89(5):476-485. Epub 2020 Sep 12.

Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, Illinois. Electronic address:

Background: Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP), have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explores polygenic scores related to the BAP.

Methods: Phenotypic and genotypic information were obtained from 2614 trios from the Simons Simplex Collection. Polygenic scores of ASD (ASD-PGSs) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and paternal ASD-PGSs were explored in relation to BAP traits and their child's ASD symptomatology.

Results: Maternal pragmatic language was related to child's social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGSs were related to the pragmatic language and rigid BAP domains.

Conclusions: Associations emerged between parent and child phenotypes, with more associations emerging in mothers than in fathers. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.
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http://dx.doi.org/10.1016/j.biopsych.2020.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901138PMC
March 2021

Properties of beta oscillations in Dup15q syndrome.

J Neurodev Disord 2020 08 13;12(1):22. Epub 2020 Aug 13.

Center for Autism Research and Treatment, Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, CA, 90024, USA.

Background: Duplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism, intellectual disability, hypotonia, and epilepsy. The 15q region harbors genes critical for brain development, particularly UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABAR) genes. We recently described an electrophysiological biomarker of the syndrome, characterized by excessive beta oscillations (12-30 Hz), resembling electroencephalogram (EEG) changes induced by allosteric modulation of GABARs. In this follow-up study, we tested a larger cohort of children with Dup15q syndrome to comprehensively examine properties of this EEG biomarker that would inform its use in future clinical trials, specifically, its (1) relation to basic clinical features, such as age, duplication type, and epilepsy; (2) relation to behavioral characteristics, such as cognition and adaptive function; (3) stability over time; and (4) reproducibility of the signal in clinical EEG recordings.

Methods: We computed EEG power and beta peak frequency (BPF) in a cohort of children with Dup15q syndrome (N = 41, age range 9-189 months). To relate EEG parameters to clinical (study 1) and behavioral features (study 2), we examined age, duplication type, epilepsy, cognition, and daily living skills (DLS) as predictors of beta power and BPF. To evaluate stability over time (study 3), we derived the intraclass correlation coefficients (ICC) from beta power and BPF computed from children with multiple EEG recordings (N = 10, age range 18-161 months). To evaluate reproducibility in a clinical setting (study 4), we derived ICCs from beta power computed from children (N = 8, age range 19-96 months), who had undergone both research EEG and clinical EEG.

Results: The most promising relationships between EEG and clinical traits were found using BPF. BPF was predicted both by epilepsy status (R = 0.11, p = 0.038) and the DLS component of the Vineland Adaptive Behavior Scale (R = 0.17, p = 0.01). Beta power and peak frequency showed high stability across repeated visits (beta power ICC = 0.93, BPF ICC = 0.92). A reproducibility analysis revealed that beta power estimates are comparable between research and clinical EEG (ICC = 0.94).

Conclusions: In this era of precision health, with pharmacological and neuromodulatory therapies being developed and tested for specific genetic etiologies of neurodevelopmental disorders, quantification and examination of mechanistic biomarkers can greatly improve clinical trials. To this end, the robust beta oscillations evident in Dup15q syndrome are clinically reproducible and stable over time. With future preclinical and computational studies that will help disentangle the underlying mechanism, it is possible that this biomarker could serve as a robust measure of drug target engagement or a proximal outcome measure in future disease modifying intervention trials.
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http://dx.doi.org/10.1186/s11689-020-09326-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425173PMC
August 2020

A framework for an evidence-based gene list relevant to autism spectrum disorder.

Nat Rev Genet 2020 06 21;21(6):367-376. Epub 2020 Apr 21.

The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.
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http://dx.doi.org/10.1038/s41576-020-0231-2DOI Listing
June 2020

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.

Cell 2020 02 23;180(3):568-584.e23. Epub 2020 Jan 23.

Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.
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http://dx.doi.org/10.1016/j.cell.2019.12.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250485PMC
February 2020

Familiality of behavioral flexibility and response inhibition deficits in autism spectrum disorder (ASD).

Mol Autism 2019 12;10:47. Epub 2019 Dec 12.

3Schiefelbusch Institute for Life Span Studies/Clinical Child Psychology Program, University of Kansas, 1000 Sunnyside Ave., Lawrence, KS 66045 USA.

Background: Diminished cognitive control, including reduced behavioral flexibility and behavioral response inhibition, has been repeatedly documented in autism spectrum disorder (ASD). We evaluated behavioral flexibility and response inhibition in probands and their parents using a family trio design to determine the extent to which these cognitive control impairments represent familial traits associated with ASD.

Methods: We examined 66 individuals with ASD (probands), 135 unaffected biological parents, and 76 typically developing controls. Participants completed a probabilistic reversal learning task (PRL) and a stop-signal task (SST) to assess behavioral flexibility and response inhibition respectively. Rates of PRL and SST errors were examined across groups, within families, and in relation to clinical and subclinical traits of ASD. Based on prior findings that subclinical broader autism phenotypic (BAP) traits may co-segregate within families and reflect heritable risk factors, we also examined whether cognitive control deficits were more prominent in families in which parents showed BAP features (BAP+).

Results: Probands and parents each showed increased rates of PRL and SST errors relative to controls. Error rates across tasks were not related. SST error rates inter-correlated among probands and their parents. PRL errors were more severe in BAP+ parents and their children relative to BAP- parents and their children. For probands of BAP+ parents, PRL and SST error rates were associated with more severe social-communication abnormalities and repetitive behaviors, respectively.

Conclusion: Reduced behavioral flexibility and response inhibition are present among probands and their unaffected parents, but represent unique familial deficits associated with ASD that track with separate clinical issues. Specifically, behavioral response inhibition impairments are familial in ASD and manifest independently from parental subclinical features. In contrast, behavioral flexibility deficits are selectively present in families with BAP characteristics, suggesting they co-segregate in families with parental subclinical social, communication, and rigid personality traits. Together, these findings provide evidence that behavioral flexibility and response inhibition impairments track differentially with ASD risk mechanisms and related behavioral traits.
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http://dx.doi.org/10.1186/s13229-019-0296-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909569PMC
June 2020

Clinical and neurocognitive issues associated with Bosch-Boonstra-Schaaf optic atrophy syndrome: A case study.

Am J Med Genet A 2020 01 15;182(1):213-218. Epub 2019 Nov 15.

Institute for Juvenile Research, University of Illinois at Chicago, Chicago, Illinois.

Nuclear receptor subfamily 2 group F member 1 (NR2F1) is an orphan receptor and transcriptional regulator that is involved in neurogenesis, visual processing and development, and cortical patterning. Alterations in NR2F1 cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a recently described autosomal dominant disorder characterized by intellectual and developmental disabilities and optic atrophy. This study describes the clinical and neurocognitive features of an individual with a de novo nonsense variant in NR2F1 (NM_005654.5:c.82C > T, p.Gln28*), identified by whole exome sequencing. The patient was diagnosed with autism spectrum disorder (ASD) and unlike most previously reported cases, he had no developmental delay, superior verbal abilities (verbal IQ = 141), and high educational attainment despite reduced nonverbal abilities (nonverbal IQ = 63). He had optic nerve hypoplasia with minimal visual impairment as well as mild dysmorphic features. Compared to both age-matched individuals with ASD and healthy controls, the patient showed reductions in manual motor speed, accuracy of saccadic eye movements, and rates of successful behavioral response inhibition. Although the majority of previously reported cases of BBSOAS have been associated with more global intellectual dysfunction, we report on a patient with selective disruption of nonverbal abilities and superior verbal abilities.
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http://dx.doi.org/10.1002/ajmg.a.61409DOI Listing
January 2020

Behavioral characterization of dup15q syndrome: Toward meaningful endpoints for clinical trials.

Am J Med Genet A 2020 01 26;182(1):71-84. Epub 2019 Oct 26.

Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.

Duplication of 15q11.2-q13.1 (dup15q syndrome) is one of the most common copy number variations associated with autism spectrum disorders (ASD) and intellectual disability (ID). As with many neurogenetic conditions, accurate behavioral assessment is challenging due to the level of impairment and heterogeneity across individuals. Large-scale phenotyping studies are necessary to inform future clinical trials in this and similar ID syndromes. This study assessed developmental and behavioral characteristics in a large cohort of children with dup15q syndrome, and examined differences based on genetic subtype and epilepsy status. Participants included 62 children (2.5-18 years). Across individuals, there was a wide range of abilities. Although adaptive behavior was strongly associated with cognitive ability, adaptive abilities were higher than cognitive scores. Measures of ASD symptoms were associated with cognitive ability, while parent report of challenging behavior was not. Both genetic subtype and epilepsy were related to degree of impairment across cognitive, language, motor, and adaptive domains. Children with isodicentric duplications and epilepsy showed the greatest impairment, while children with interstitial duplications showed the least. On average, participants with epilepsy experienced seizures over 53% of their lives, and half of children with epilepsy had infantile spasms. Parents of children with isodicentric duplications reported more concerns regarding challenging behaviors. Future trials in ID syndromes should employ a flexible set of assessments, allowing each participant to receive assessments that capture their skills. Multiple sources of information should be considered, and the impact of language and cognitive ability should be taken into consideration when interpreting results.
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http://dx.doi.org/10.1002/ajmg.a.61385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334030PMC
January 2020

A Bayesian framework that integrates multi-omics data and gene networks predicts risk genes from schizophrenia GWAS data.

Nat Neurosci 2019 05 15;22(5):691-699. Epub 2019 Apr 15.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.

Genome-wide association studies (GWAS) have identified more than 100 schizophrenia (SCZ)-associated loci, but using these findings to illuminate disease biology remains a challenge. Here we present integrative risk gene selector (iRIGS), a Bayesian framework that integrates multi-omics data and gene networks to infer risk genes in GWAS loci. By applying iRIGS to SCZ GWAS data, we predicted a set of high-confidence risk genes, most of which are not the nearest genes to the GWAS index variants. High-confidence risk genes account for a significantly enriched heritability, as estimated by stratified linkage disequilibrium score regression. Moreover, high-confidence risk genes are predominantly expressed in brain tissues, especially prenatally, and are enriched for targets of approved drugs, suggesting opportunities to reposition existing drugs for SCZ. Thus, iRIGS can leverage accumulating functional genomics and GWAS data to advance our understanding of SCZ etiology and potential therapeutics.
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http://dx.doi.org/10.1038/s41593-019-0382-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646046PMC
May 2019

Lovastatin Treatment of a Patient with a Protein Truncating Variant.

J Child Adolesc Psychopharmacol 2019 05 4;29(4):321-322. Epub 2019 Apr 4.

1 Department of Psychiatry, Institute for Juvenile Research, University of Illinois at Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1089/cap.2018.0159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533776PMC
May 2019

Phenotypic association of 15q11.2 CNVs of the region of breakpoints 1-2 (BP1-BP2) in a large cohort of samples referred for genetic diagnosis.

J Hum Genet 2019 Mar 12;64(3):253-255. Epub 2018 Dec 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.

In view of conflicting reports on the pathogenicity of 15q11.2 CNVs of the breakpoints 1-2 (BP1-BP2) region and lack of association with a specific phenotype, we collected phenotypic data on 51,462 patients referred for genetic testing at two centers (Magee-Womens Hospital of UPMC and Baylor Genetics Laboratories, Baylor College of Medicine). Using array CGH, 262 patients with deletions and 215 with duplications were identified and tested for their association with four phenotypes (developmental delay, dysmorphic features, autism group of disorders, and epilepsy/seizures). Only association of deletions with dysmorphic features was observed (P = 0.013) with low penetrance (3.8%). Our results, viewed in the context of other reports suggesting the lack of a clear phenotypic outcome, underscore the need for detailed phenotypic studies to better understand the pathogenicity of 15q11.2 (BP1-BP2) CNVs.
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http://dx.doi.org/10.1038/s10038-018-0543-7DOI Listing
March 2019

Maternal Serotonin Levels Are Associated With Cognitive Ability and Core Symptoms in Autism Spectrum Disorder.

J Am Acad Child Adolesc Psychiatry 2018 11 24;57(11):867-875. Epub 2018 Sep 24.

New York State Psychiatric Institute, New York, NY, and the Center for Autism and the Developing Brain, New York-Presbyterian Hospital, White Plains, NY. They are also with the Sackler Institute for Developmental Psychobiology; Columbia University Medical Center, New York, NY. Electronic address:

Objective: The serotonin (5-hydroxytryptamine [HT]) system has long been implicated in autism spectrum disorder (ASD). Whole-blood 5-HT level (WB5-HT) is a stable, heritable biomarker that is elevated in more than 25% of children with ASD. Recent findings indicate that the maternal 5-HT system may influence embryonic neurodevelopment, but maternal WB5-HT has not been examined in relation to ASD phenotypes.

Method: WB5-HT levels were obtained from 181 individuals (3-27 years of age) diagnosed with ASD, 99 of their fathers, and 119 of their mothers. Standardized assessments were used to evaluate cognitive, behavioral, and language phenotypes.

Results: Exploratory regression analyses found relationships between maternal WB5-HT and nonverbal IQ (NVIQ), Autism Diagnostic Interview-Revised (ADI-R) Nonverbal Communication Algorithm scores, and overall adaptive function on the Vineland Adaptive Behavior Scales-II. Latent class analysis identified a three-class structure in the assessment data, describing children with low, intermediate, and high severity across measures of behavior, cognition, and adaptive function. Mean maternal WB5-HT differed across classes, with the lowest maternal WB5-HT levels seen in the highest-severity group (Welch F = 17.394, p < .001). Paternal and proband WB5-HT did not differ between classes.

Conclusion: Maternal WB5-HT is associated with neurodevelopmental outcomes in offspring with ASD. Prospective, longitudinal studies will be needed to better understand the relationship between the function of the maternal serotonin system during pregnancy and brain development. Further studies in animal models may be able to reveal the mechanisms underlying these findings.
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http://dx.doi.org/10.1016/j.jaac.2018.06.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531860PMC
November 2018

Cognitive mechanisms of inhibitory control deficits in autism spectrum disorder.

J Child Psychol Psychiatry 2018 05 20;59(5):586-595. Epub 2017 Oct 20.

Schiefelbusch Institute for Life Span Studies and Clinical Child Psychology Program, University of Kansas, Lawrence, KS, USA.

Background: Inhibitory control deficits are common in autism spectrum disorder (ASD) and associated with more severe repetitive behaviors. Inhibitory control deficits may reflect slower execution of stopping processes, or a reduced ability to delay the onset of behavioral responses in contexts of uncertainty. Previous studies have documented relatively spared stopping processes in ASD, but whether inhibitory control deficits in ASD reflect failures to delay response onset has not been systematically assessed. Further, while improvements in stopping abilities and response slowing are seen through adolescence/early adulthood in health, their development in ASD is less clear.

Methods: A stop-signal test (SST) was administered to 121 individuals with ASD and 76 age and IQ-matched healthy controls (ages 5-28). This test included 'GO trials' in which participants pressed a button when a peripheral target appeared and interleaved 'STOP trials' in which they were cued to inhibit button-presses when a stop-signal appeared at variable times following the GO cue. STOP trial accuracy, RT of the stopping process (SSRT), and reaction time (RT) slowing during GO trials were examined.

Results: Relative to controls, individuals with ASD had reduced accuracy on STOP trials. SSRTs were similar across control and ASD participants, but RT slowing was reduced in patients compared to controls. Age-related increases in stopping ability and RT slowing were attenuated in ASD. Reduced stopping accuracy and RT slowing were associated with more severe repetitive behaviors in ASD.

Discussion: Our findings show that inhibitory control deficits in ASD involve failures to strategically delay behavioral response onset. These results suggest that reduced preparatory behavioral control may underpin inhibitory control deficits as well as repetitive behaviors in ASD. Typical age-related improvements in inhibitory control during late childhood/early adolescence are reduced in ASD, highlighting an important developmental window during which treatments may mitigate cognitive alterations contributing to repetitive behaviors.
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http://dx.doi.org/10.1111/jcpp.12837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906199PMC
May 2018

De novo unbalanced translocation (4p duplication/8p deletion) in a patient with autism, OCD, and overgrowth syndrome.

Am J Med Genet A 2017 Jun 13;173(6):1656-1662. Epub 2017 Apr 13.

Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.

Chromosomal abnormalities, such as unbalanced translocations and copy number variants (CNVs), are found in autism spectrum disorders (ASDs) [Sanders et al. (2011) Neuron 70: 863-885]. Many chromosomal abnormalities, including sub microscopic genomic deletions and duplications, are missed by G-banded karyotyping or Fragile X screening alone and are picked up by chromosomal microarrays [Shen et al. (2010) Pediatrics 125: e727-735]. Translocations involving chromosomes 4 and 8 are possibly the second most frequent translocation in humans and are often undetected in routine cytogenetics [Giglio et al. (2002) Circulation 102: 432-437]. Deletions of 4p16 have been associated with Wolf-Hirschhorn syndrome while 4p16 duplications have been associated with an overgrowth syndrome and mild to moderate mental retardation [Partington et al. (1997) Journal of Medical Genetics 34: 719-728]. The 8p23.3 region contains the autism candidate gene DLGAP2, which can contribute to autism when disrupted [Marshall et al. (2008) The American Journal of Human Genetics 82: 477-488] . There has been a case report of a family with autism spectrum disorder (ASD), prominent obsessional behavior, and overgrowth in patients with der (8) t (4;8) p (16;23) [Partington et al. (1997)]. This is an independent report of a male patient with autism, obsessive compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), and an overgrowth syndrome, whose de novo unbalanced translocation der (8) t (4;8) p (16.1→ter; 23.1→ter) was initially missed by routine cytogenetics but detected with SNP microarray, allowing higher resolution of translocation breakpoints.
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http://dx.doi.org/10.1002/ajmg.a.38171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444998PMC
June 2017

Is there sexual dimorphism of hyperserotonemia in autism spectrum disorder?

Autism Res 2017 Aug 12;10(8):1417-1423. Epub 2017 Apr 12.

Department of Psychiatry, Columbia University Medical Center, New York.

Approximately 30% of individuals with autism spectrum disorder (ASD) have elevated whole blood serotonin (5-HT) levels. Genetic linkage and association studies of ASD and of whole blood 5-HT levels as a quantitative trait have revealed sexual dimorphism. Few studies have examined the presence of a sex difference on hyperserotonemia within ASD. To assess whether the rate of hyperserotonemia is different in males than in females with ASD, we measured whole blood 5-HT levels in 292 children and adolescents with ASD, the largest sample in which this biomarker has been assessed. Based upon previous work suggesting that hyperserotonemia is more common prior to puberty, we focused our analysis on the 182 pre-pubertal children with ASD. 42% of pre-pubertal participants were within the hyperserotonemia range. In this population, we found that males were significantly more likely to manifest hyperserotonemia than females (P = 0.03). As expected, no significant difference was found in the post-pubertal population. Additional work will be needed to replicate this intriguing finding and to understand whether it could potentially explain differences in patterns of ASD risk between males and females. Autism Res 2017, 10: 1417-1423. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/aur.1791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568968PMC
August 2017

Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.

Mol Autism 2017 21;8:14. Epub 2017 Mar 21.

Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN USA.

Background: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown.

Methods: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements.

Results: Combined with published ASD DNVs, we identified as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs ( and ). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-β pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD.

Conclusions: Our study identified as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes.
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http://dx.doi.org/10.1186/s13229-017-0130-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361831PMC
May 2017

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.

Nat Neurosci 2017 Apr 6;20(4):602-611. Epub 2017 Mar 6.

The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.

We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.
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http://dx.doi.org/10.1038/nn.4524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501701PMC
April 2017

Pharmacogenomics of autism spectrum disorder.

Pharmacogenomics 2017 Mar 22;18(4):403-414. Epub 2017 Feb 22.

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and interactions as well as restricted, repetitive behaviors and interests. Pharmacologic interventions are often needed to manage irritability, aggressive behaviors and hyperactivity. Pharmacogenomic studies have investigated genetic associations with treatment response and side effects in an attempt to better understand drug mechanisms in hopes of optimizing the balance of symptom improvement versus side effects. The majority of pharmacogenomic studies to date have focused on antipsychotics, antidepressants and stimulants that are the most commonly utilized medication classes for ASD. This review is a comprehensive examination of the existing pharmacogenomic studies in ASD highlighting the current state of knowledge regarding genetic variation influencing pharmacokinetics and pharmacodynamics, and associated clinical outcomes.
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http://dx.doi.org/10.2217/pgs-2016-0167DOI Listing
March 2017

A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome.

PLoS One 2016 15;11(12):e0167179. Epub 2016 Dec 15.

Center for Autism Research and Treatment University of California, Los Angeles Semel Institute for Neuroscience 760 Westwood Plaza, Suite A7-452 Los Angeles, California United States of America.

Background: Duplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome.

Methods: In the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11), age-and-IQ-matched children with ASD (n = 10) and age-matched typically developing (TD) children (n = 9) and computed relative power in 6 frequency bands for 9 regions of interest (ROIs). Group comparisons were made using a repeated measures analysis of variance. In the second study, we recorded spontaneous EEG from a larger cohort of individuals with Dup15q syndrome (n = 27) across two sites and examined age, epilepsy, and duplication type as predictors of beta power using simple linear regressions.

Results: In the first study, spontaneous beta1 (12-20 Hz) and beta2 (20-30 Hz) power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta (1-4 Hz) was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (|d| > 1). In the second study, we found that beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome.

Conclusions: Here, we have identified an electrophysiological biomarker of Dup15q syndrome that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials. Future work will investigate the genetic and neural underpinnings of this electrophysiological signature as well as the functional consequences of excessive beta oscillations in Dup15q syndrome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167179PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157977PMC
June 2017

ASD and Genetic Associations with Receptors for Oxytocin and Vasopressin-, and .

Front Neurosci 2016 22;10:516. Epub 2016 Nov 22.

Department of Psychiatry, University of Minnesota Minneapolis, MN, USA.

There are limited treatments available for autism spectrum disorder (ASD). Studies have reported significant associations between the receptor genes of oxytocin (OT) and vasopressin (AVP) and ASD diagnosis, as well as ASD-related phenotypes. Researchers have also found the manipulation of these systems affects social and repetitive behaviors, core characteristics of ASD. Consequently, research involving the oxytocin/vasopressin pathways as intervention targets has increased. Therefore, further examination into the relationship between these neuropeptides and ASD was undertaken. In this study, we examined associations between variants in the receptor genes of vasopressin (), oxytocin (), and ASD diagnosis along with related subphenotypes. Probands were assessed using Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and clinical DSM-IV-TR criteria. Single nucleotide polymorphisms (SNPs) in and , and microsatellites in were genotyped in ~200 families with a proband with ASD. Family-based association testing (FBAT) was utilized to determine associations between variants and ASD. Haplotypes composed of SNPs (i.e., rs53576-rs2254298-rs2268493) were also analyzed due to previously published associations. Using the additive inheritance model in FBAT we found associations between SNPs (rs28632197, = 0.005, rs35369693, = 0.025) and diagnosis. As in other studies, rs2268493 ( = 0.050) was associated with diagnosis. rs2268493 was also associated with ASD subphenotypes of social withdrawal ( = 0.013) and Insistence on Sameness ( = 0.039). Further analyses demonstrated that the haplotype, rs2254298-rs2268493 was found to be significantly associated with diagnosis (A-T; = 0.026). FBAT was also used to analyze microsatellites (RS1 and RS3). Both length variants were found to be associated with restrictive, repetitive behaviors, but not overall diagnosis. Correction for multiple comparisons was performed for SNPs tested in each gene region, only SNPs remained significantly associated with ASD diagnosis. Autism is a heterogeneous disorder with many genes and pathways that contribute to its development. SNPs and microsatellites in the receptor genes of OT and AVP are associated with ASD diagnosis and measures of social behavior as well as restricted repetitive behaviors. We reported a novel association with ASD and SNPs. Understanding of genotype-phenotype relationships may be helpful in the development of pharmacological interventions for the OT/AVP system.
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http://dx.doi.org/10.3389/fnins.2016.00516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118619PMC
November 2016

Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial.

Neuropsychopharmacology 2017 Jun 17;42(7):1390-1398. Epub 2016 Oct 17.

Seaside Therapeutics, Cambridge, MA, USA.

Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist arbaclofen improved social avoidance symptoms in FXS. A pilot open-label trial of arbaclofen suggested similar benefits in ASD. We therefore evaluated arbaclofen in a randomized, placebo-controlled, phase 2 study of 150 participants, aged 5-21 years, with ASD. No difference from placebo was detected on the primary outcome measure, the parent-rated Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale. However, a specified secondary analysis found improvement on the clinician-rated Clinical Global Impression of Severity. An exploratory post hoc analysis of participants with a consistent rater across the trial revealed greater improvement in the Vineland Adaptive Behavior Scales II socialization domain in participants receiving arbaclofen. Affect lability (11%) and sedation (9%) were the most common adverse events. In this exploratory study, secondary analyses suggest that arbaclofen may have the potential to improve symptoms in some children with ASD, but further study will be needed to replicate and extend these initial findings.
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http://dx.doi.org/10.1038/npp.2016.237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436109PMC
June 2017

STAMS: STRING-assisted module search for genome wide association studies and application to autism.

Bioinformatics 2016 12 19;32(24):3815-3822. Epub 2016 Aug 19.

Departments of Bioengineering and Genetics, Stanford University, Stanford, CA, USA.

Motivation: Analyzing genome wide association data in the context of biological pathways helps us understand how genetic variation influences phenotype and increases power to find associations. However, the utility of pathway-based analysis tools is hampered by undercuration and reliance on a distribution of signal across all of the genes in a pathway. Methods that combine genome wide association results with genetic networks to infer the key phenotype-modulating subnetworks combat these issues, but have primarily been limited to network definitions with yes/no labels for gene-gene interactions. A recent method (EW_dmGWAS) incorporates a biological network with weighted edge probability by requiring a secondary phenotype-specific expression dataset. In this article, we combine an algorithm for weighted-edge module searching and a probabilistic interaction network in order to develop a method, STAMS, for recovering modules of genes with strong associations to the phenotype and probable biologic coherence. Our method builds on EW_dmGWAS but does not require a secondary expression dataset and performs better in six test cases.

Results: We show that our algorithm improves over EW_dmGWAS and standard gene-based analysis by measuring precision and recall of each method on separately identified associations. In the Wellcome Trust Rheumatoid Arthritis study, STAMS-identified modules were more enriched for separately identified associations than EW_dmGWAS (STAMS P-value 3.0 × 10; EW_dmGWAS- P-value = 0.8). We demonstrate that the area under the Precision-Recall curve is 5.9 times higher with STAMS than EW_dmGWAS run on the Wellcome Trust Type 1 Diabetes data.

Availability And Implementation: STAMS is implemented as an R package and is freely available at https://simtk.org/projects/stams CONTACT: [email protected] information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btw530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167061PMC
December 2016

The impact of genotype calling errors on family-based studies.

Sci Rep 2016 06 22;6:28323. Epub 2016 Jun 22.

Division of Pulmonary Medicine, Allergy and Immunology; Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224, USA.

Family-based sequencing studies have unique advantages in enriching rare variants, controlling population stratification, and improving genotype calling. Standard genotype calling algorithms are less likely to call rare variants correctly, often mistakenly calling heterozygotes as reference homozygotes. The consequences of such non-random errors on association tests for rare variants are unclear, particularly in transmission-based tests. In this study, we investigated the impact of genotyping errors on rare variant association tests of family-based sequence data. We performed a comprehensive analysis to study how genotype calling errors affect type I error and statistical power of transmission-based association tests using a variety of realistic parameters in family-based sequencing studies. In simulation studies, we found that biased genotype calling errors yielded not only an inflation of type I error but also a power loss of association tests. We further confirmed our observation using exome sequence data from an autism project. We concluded that non-symmetric genotype calling errors need careful consideration in the analysis of family-based sequence data and we provided practical guidance on ameliorating the test bias.
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http://dx.doi.org/10.1038/srep28323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916415PMC
June 2016

Variants in Adjacent Oxytocin/Vasopressin Gene Region and Associations with ASD Diagnosis and Other Autism Related Endophenotypes.

Front Neurosci 2016 12;10:195. Epub 2016 May 12.

Department of Psychiatry, University of Minnesota Minneapolis, MN, USA.

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 endophenotypes were also noted: OXT rs6133010 was associated with IQ (full scale IQ, p = 0.008; nonverbal IQ, p = 0.010, verbal IQ, p = 0.006); and OXT rs4813625 and OXT rs877172 were associated with WB5HT levels (EA, p = 0.027 and p = 0.033, respectively). Additionally, we measured plasma OT (pOT) levels in a subsample (N = 54). RESULTS show the three polymorphisms, OXT rs6084258, OXT rs11697250, and OXT rs877172, have significant association with pOT (EA, p = 0.011, p = 0.010, and p = 0.002, 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.
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http://dx.doi.org/10.3389/fnins.2016.00195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863894PMC
May 2016

Commentary on "Platelet Studies in Autism Spectrum Disorder Patients and First-Degree Relatives".

Mol Autism 2016 29;7:20. Epub 2016 Mar 29.

Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL USA.

We comment on the recent report entitled "Platelet Studies in Autism Spectrum Disorder Patients and First-Degree Relatives" [Molecular Autism 2015;6:57]. We find it commendable that the authors have investigated platelet factors potentially involved in the well-replicated observation of platelet hyperserotonemia in autism. However, we believe the results need a fuller discussion in the context of prior studies, think that certain aspects of the interpretation need to be reassessed, and attempt to provide a framework for further research in this area.
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http://dx.doi.org/10.1186/s13229-016-0086-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812610PMC
July 2016

Confirmation of the Factor Structure and Measurement Invariance of the Children's Scale of Hostility and Aggression: Reactive/Proactive in Clinic-Referred Children With and Without Autism Spectrum Disorder.

J Child Adolesc Psychopharmacol 2016 Feb 8;26(1):10-8. Epub 2016 Jan 8.

1 Department of Psychology, The Ohio State University , Columbus, Ohio.

Objective: The measurement of aggression in its different forms (e.g., physical and verbal) and functions (e.g., impulsive and instrumental) is given little attention in subjects with developmental disabilities (DD). In this study, we confirm the factor structure of the Children's Scale for Hostility and Aggression: Reactive/Proactive (C-SHARP) and demonstrate measurement invariance (consistent performance across clinical groups) between clinic-referred groups with and without autism spectrum disorder (ASD). We also provide evidence of the construct validity of the C-SHARP.

Methods: Caregivers provided C-SHARP, Child Behavior Checklist (CBCL), and Proactive/Reactive Rating Scale (PRRS) ratings for 644 children, adolescents, and young adults 2-21 years of age. Five types of measurement invariance were evaluated within a confirmatory factor analytic framework. Associations among the C-SHARP, CBCL, and PRRS were explored.

Results: The factor structure of the C-SHARP had a good fit to the data from both groups, and strict measurement invariance between ASD and non-ASD groups was demonstrated (i.e., equivalent structure, factor loadings, item intercepts and residuals, and latent variance/covariance between groups). The C-SHARP Problem Scale was more strongly associated with CBCL Externalizing than with CBCL Internalizing, supporting its construct validity. Subjects classified with the PRRS as both Reactive and Proactive had significantly higher C-SHARP Proactive Scores than those classified as Reactive only, who were rated significantly higher than those classified by the PRRS as Neither Reactive nor Proactive. A similar pattern was observed for the C-SHARP Reactive Score.

Conclusions: This study provided evidence of the validity of the C-SHARP through confirmation of its factor structure and its relationship with more established scales. The demonstration of measurement invariance demonstrates that differences in C-SHARP factor scores were the result of differences in the construct rather than to error or unmeasured/nuisance variables. These data suggest that the C-SHARP is useful for quantifying subtypes of aggressive behavior in children, adolescents, and young adults with DD.
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http://dx.doi.org/10.1089/cap.2015.0098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779278PMC
February 2016

Separating Family-Level and Direct Exposure Effects of Smoking During Pregnancy on Offspring Externalizing Symptoms: Bridging the Behavior Genetic and Behavior Teratologic Divide.

Behav Genet 2016 05 18;46(3):389-402. Epub 2015 Nov 18.

Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, 633 N. St. Clair Street, 19th Floor, Chicago, IL, 60611, USA.

Maternal smoking during pregnancy (MSDP) has been robustly associated with externalizing problems and their developmental precursors in offspring in studies using behavioral teratologic designs (Wakschlag et al., Am J Public Health 92(6):966-974, 2002; Espy et al., Dev Psychol 47(1):153-169, 2011). In contrast, the use of behavior genetic approaches has shown that the effects commonly attributed to MSDP can be explained by family-level variables (D'Onofrio et al., Dev Psychopathol 20(01):139-164, 2008). Reconciling these conflicting findings requires integration of these study designs. We utilize longitudinal data on a preschool proband and his/her sibling from the Midwest Infant Development Study-Preschool (MIDS-P) to test for teratologic and family level effects of MSDP. We find considerable variation in prenatal smoking patterns both within and across pregnancies within families, indicating that binary smoking measures are not sufficiently capturing exposure. Structural equation models indicate that both conduct disorder and oppositional defiant disorder symptoms showed unique effects of MSDP over and above family level effects. Blending high quality exposure measurement with a within-family design suggests that it is premature to foreclose the possibility of a teratologic effect of MSDP on externalizing problems. Implications and recommendations for future studies are discussed.
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http://dx.doi.org/10.1007/s10519-015-9762-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860106PMC
May 2016

Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications.

Acta Neuropathol Commun 2015 Oct 13;3:63. Epub 2015 Oct 13.

Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, Staten Island, NY, USA.

Introduction: Autism is diagnosed in numerous genetic and genomic developmental disorders associated with an overlap in high-risk genes and loci that underlie intellectual disability (ID) and epilepsy. The aim of this stereological study of neuronal soma volume in 25 brain structures and their subdivisions in eight individuals 9 to 26 years of age who were diagnosed with chromosome 15q11.2-13.1 duplication syndrome [dup(15)], autism, ID and epilepsy; eight age-matched subjects diagnosed with autism of unknown etiology (idiopathic autism) and seven control individuals was to establish whether defects of neuronal soma growth are a common denominator of developmental pathology in idiopathic and syndromic autism and how genetic modifications alter the trajectory of neuronal soma growth in dup(15) autism.

Results: Application of the Nucleator software to estimate neuronal size revealed significant neuronal soma volume deficits in 11 of 25 structures and their subregions (44 %) in subjects diagnosed with dup(15) autism, including consistent neuronal soma volume deficits in the limbic system (sectors CA2, 3 and 4 in Ammon's horn, the second and third layers of the entorhinal cortex and in the amygdala), as well as in the thalamus, nucleus accumbens, external globus pallidus, and Ch3 nucleus in the magnocellular basal complex, and in the inferior olive in the brainstem. The second feature distinguishing dup(15) autism was persistent neuronal soma deficits in adolescents and young adults, whereas in idiopathic autism, neuronal volume deficit is most prominent in 4- to 8-year-old children but affects only a few brain regions in older subjects.

Conclusions: This study demonstrates that alterations in the trajectory of neuronal growth throughout the lifespan are a core pathological features of idiopathic and syndromic autism. However, dup(15) causes persistent neuronal volume deficits in adolescence and adulthood, with prominent neuronal growth deficits in all major compartments of the limbic system. The more severe neuronal nuclear and cytoplasic volume deficits in syndromic autism found in this study and the more severe focal developmental defects in the limbic system in dup(15) previously reported in this cohort may contribute to the high prevalence of early onset intractable epilepsy and sudden unexpected death in epilepsy.
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http://dx.doi.org/10.1186/s40478-015-0241-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603300PMC
October 2015

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.

Neuron 2015 Sep;87(6):1215-1233

Center for Autism and the Developing Brain, Weill Cornell Medical College, White Plains, NY 10605, USA.

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).
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http://dx.doi.org/10.1016/j.neuron.2015.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624267PMC
September 2015
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