Publications by authors named "Jeff Munson"

27 Publications

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Hyaluronidase Impairs Neutrophil Function and Promotes Group B Invasion and Preterm Labor in Nonhuman Primates.

mBio 2021 01 5;12(1). Epub 2021 Jan 5.

Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA

Invasive bacterial infections during pregnancy are a major risk factor for preterm birth, stillbirth, and fetal injury. Group B streptococci (GBS) are Gram-positive bacteria that asymptomatically colonize the lower genital tract but infect the amniotic fluid and induce preterm birth or stillbirth. Experimental models that closely emulate human pregnancy are pivotal for the development of successful strategies to prevent these adverse pregnancy outcomes. Using a unique nonhuman primate model that mimics human pregnancy and informs temporal events surrounding amniotic cavity invasion and preterm labor, we show that the animals inoculated with hyaluronidase (HylB)-expressing GBS consistently exhibited microbial invasion into the amniotic cavity, fetal bacteremia, and preterm labor. Although delayed cytokine responses were observed at the maternal-fetal interface, increased prostaglandin and matrix metalloproteinase levels in these animals likely mediated preterm labor. HylB-proficient GBS dampened reactive oxygen species production and exhibited increased resistance to neutrophils compared to an isogenic mutant. Together, these findings demonstrate how a bacterial enzyme promotes GBS amniotic cavity invasion and preterm labor in a model that closely resembles human pregnancy. Group B streptococci (GBS) are bacteria that commonly reside in the female lower genital tract as asymptomatic members of the microbiota. However, during pregnancy, GBS can infect tissues at the maternal-fetal interface, leading to preterm birth, stillbirth, or fetal injury. Understanding how GBS evade host defenses during pregnancy is key to developing improved preventive therapies for these adverse outcomes. In this study, we used a unique nonhuman primate model to show that an enzyme secreted by GBS, hyaluronidase (HylB) promotes bacterial invasion into the amniotic cavity and fetus. Although delayed immune responses were seen at the maternal-fetal interface, animals infected with hyaluronidase-expressing GBS exhibited premature cervical ripening and preterm labor. These observations reveal that HylB is a crucial GBS virulence factor that promotes bacterial invasion and preterm labor in a pregnancy model that closely emulates human pregnancy. Therefore, hyaluronidase inhibitors may be useful in therapeutic strategies against ascending GBS infection.
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http://dx.doi.org/10.1128/mBio.03115-20DOI Listing
January 2021

Interaction of Treatment Intensity and Autism Severity on Frequency and Maturity of Spontaneous Communication in Toddlers with Autism Spectrum Disorder.

Autism Res 2020 11 24;13(11):1902-1912. Epub 2020 Oct 24.

Huntington Beach, California, USA.

This study tested whether the effect of treatment intensity or treatment style on children's frequency and maturity of spontaneous communication varied by initial severity of disability. Eighty-seven toddlers with autism spectrum disorders were randomly assigned to either (a) 15 hrs per week of discrete trial teaching (DTT), (b) 25 hrs per week of DTT, (c) 15 hrs per week of a naturalistic developmental behavioral intervention (NDBI), or (d) 25 hrs per week of NDBI. Trained research staff implemented the 1:1 treatments in homes or educational centers over 12 months. We quantified the frequency and maturity of spontaneous communication during monthly 6-min communication samples. We quantified disability severity at Time 1 using the developmental quotient from the Mullen Scales of Early Learning and the total calibrated severity score from the Autism Diagnostic Observation Schedule-second edition. Higher levels of treatment intensity (i.e., more hours per week) benefited frequency and maturity of spontaneous communication growth rate only in children with relatively mild autism symptoms. Other results were nonsignificant. Autism Res 2020, 13: 1902-1912. © 2020 International Society for Autism Research and Wiley Periodicals LLC LAY SUMMARY: Eighty-seven toddlers with autism spectrum disorders were randomly assigned to 15 hrs per week of discrete trial teaching (DTT), 25 hrs per week of DTT, 15 hrs per week of a naturalistic developmental behavioral intervention (NDBI), or 25 hrs per week of NDBI. Trained research staff implemented the treatments in homes or educational centers over 12 months. More hours of treatment per week benefited frequency and maturity of spontaneous communication growth rate only in children with relatively mild autism symptoms. Other results were nonsignificant.
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http://dx.doi.org/10.1002/aur.2416DOI Listing
November 2020

A Multisite Randomized Controlled Trial Comparing the Effects of Intervention Intensity and Intervention Style on Outcomes for Young Children With Autism.

J Am Acad Child Adolesc Psychiatry 2020 Aug 24. Epub 2020 Aug 24.

University of California, Los Angeles.

Objective: This randomized, multisite, intent-to-treat study tested the effects of 2 levels of treatment intensity (number of hours) and 2 treatment styles on the progress of young children with autism spectrum disorder (ASD). We predicted that initial severity of developmental delay or autism symptoms would moderate the effects of intensity and style on progress in 4 domains: autism symptom severity, expressive communication, receptive language, and nonverbal ability.

Method: A total of 87 children with ASD, mean age 23.4 months, were assigned to 1 of 2 intervention styles (naturalistic developmental/behavioral or discrete trial teaching), each delivered for either 15 or 25 hours per week of 1:1 intervention for 12 months by trained research staff. All caregivers received coaching twice monthly. Children were assessed at 4 timepoints. Examiners and coders were naive to treatment assignment.

Results: Neither style nor intensity had main effects on the 4 outcome variables. In terms of moderating the effects of initial severity of developmental delay and of autism symptom severity, neither moderated the effects of treatment style on progress in any of the 4 domains. In terms of treatment intensity, initial severity moderated effect of treatment intensity on only 1 domain, namely, change in autism symptom severity; in a secondary analysis, this effect was found in only 1 site.

Conclusion: Neither treatment style nor intensity had overall effects on child outcomes in the 4 domains examined. Initial severity did not predict better response to 1 intervention style than to another. We found very limited evidence that initial severity predicted better response to 25 vs 15 hours per week of intervention in the domains studied.

Clinical Trial Registration Information: Intervention Effects of Intensity and Delivery Style for Toddlers With Autism: https://clinicaltrials.gov/; NCT02272192.
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http://dx.doi.org/10.1016/j.jaac.2020.06.013DOI Listing
August 2020

Low Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 Among Pregnant and Postpartum Patients With Universal Screening in Seattle, Washington.

Clin Infect Dis 2021 03;72(5):869-872

Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Washington, Seattle, Washington, USA.

We found low prevalence of SARS-CoV-2 (2.7% [5/188]) among pregnant and postpartum patients with universal testing. Prevalence among symptomatic patients was similar under initial targeted screening (22.2% [4/18]) and universal approaches (19.1% [8/42]). Among 170 asymptomatic patients, 2 were positive or inconclusive, respectively; repeat testing at 24 hours was negative.
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http://dx.doi.org/10.1093/cid/ciaa675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314151PMC
March 2021

Clinical characteristics of 46 pregnant women with a severe acute respiratory syndrome coronavirus 2 infection in Washington State.

Am J Obstet Gynecol 2020 12 19;223(6):911.e1-911.e14. Epub 2020 May 19.

Department of Global Health, University of Washington, Seattle, WA; Department of Obstetrics and Gynecology, University of Washington, Seattle, WA. Electronic address:

Background: The impact of coronavirus disease 2019 on pregnant women is incompletely understood, but early data from case series suggest a variable course of illness from asymptomatic or mild disease to maternal death. It is unclear whether pregnant women manifest enhanced disease similar to influenza viral infection or whether specific risk factors might predispose to severe disease.

Objective: To describe maternal disease and obstetrical outcomes associated with coronavirus disease 2019 in pregnancy to rapidly inform clinical care.

Study Design: This is a retrospective study of pregnant patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection from 6 hospital systems in Washington State between Jan. 21, 2020, and April 17, 2020. Demographics, medical and obstetrical history, and coronavirus disease 2019 encounter data were abstracted from medical records.

Results: A total of 46 pregnant patients with a severe acute respiratory syndrome coronavirus 2 infection were identified from hospital systems capturing 40% of births in Washington State. Nearly all pregnant individuals with a severe acute respiratory syndrome coronavirus 2 infection were symptomatic (93.5%, n=43) and the majority were in their second or third trimester (43.5% [n=20] and 50.0% [n=23], respectively). Symptoms resolved in a median of 24 days (interquartile range, 13-37). Notably, 7 women were hospitalized (16%) including 1 admitted to the intensive care unit. A total of 6 cases (15%) were categorized as severe coronavirus disease 2019 with nearly all patients being either overweight or obese before pregnancy or with asthma or other comorbidities. Of the 8 deliveries that occurred during the study period, there was 1 preterm birth at 33 weeks' gestation to improve pulmonary status in a woman with class III obesity, and 1 stillbirth of unknown etiology.

Conclusion: Severe coronavirus disease 2019 developed in approximately 15% of pregnant patients and occurred primarily in overweight or obese women with underlying conditions. Obesity and coronavirus disease 2019 may synergistically increase risk for a medically indicated preterm birth to improve maternal pulmonary status in late pregnancy. These findings support categorizing pregnant patients as a higher-risk group, particularly those with chronic comorbidities.
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http://dx.doi.org/10.1016/j.ajog.2020.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234933PMC
December 2020

A Broad Spectrum Chemokine Inhibitor Prevents Preterm Labor but Not Microbial Invasion of the Amniotic Cavity or Neonatal Morbidity in a Non-human Primate Model.

Front Immunol 2020 30;11:770. Epub 2020 Apr 30.

Department of Obstetrics & Gynecology, University of Washington, Seattle, WA, United States.

Leukocyte activation within the chorioamniotic membranes is strongly associated with inflammation and preterm labor (PTL). We hypothesized that prophylaxis with a broad-spectrum chemokine inhibitor (BSCI) would downregulate the inflammatory microenvironment induced by Group B Streptococcus (GBS, ) to suppress PTL and microbial invasion of the amniotic cavity (MIAC). To correlate BSCI administration with PTL and MIAC, we used a unique chronically catheterized non-human primate model of Group B Streptococcus (GBS)-induced PTL. In the early third trimester (128-138 days gestation; ~29-32 weeks human pregnancy), animals received choriodecidual inoculations of either: (1) saline ( = 6), (2) GBS, 1-5 × 10 colony forming units (CFU)/ml; = 5), or (3) pre-treatment and daily infusions of a BSCI (10 mg/kg intravenous and intra-amniotic) with GBS (1-5 × 10 CFU/ml; = 4). We measured amniotic cavity pressure (uterine contraction strength) and sampled amniotic fluid (AF) and maternal blood serially and cord blood at delivery. Cesarean section was performed 3 days post-inoculation or earlier for PTL. Data analysis used Fisher's exact test, Wilcoxon rank sum and one-way ANOVA with Bonferroni correction. Saline inoculation did not induce PTL or infectious sequelae. In contrast, GBS inoculation typically induced PTL (4/5, 80%), MIAC and fetal bacteremia (3/5; 60%). Remarkably, PTL did not occur in the BSCI+GBS group (0/4, 0%; = 0.02 vs. GBS), despite MIAC and fetal bacteremia in all cases (4/4; 100%). Compared to the GBS group, BSCI prophylaxis was associated with significantly lower cytokine levels including lower IL-8 in amniotic fluid ( = 0.03), TNF-α in fetal plasma ( < 0.05), IFN-α and IL-7 in the fetal lung ( = 0.02) and IL-18, IL-2, and IL-7 in the fetal brain ( = 0.03). Neutrophilic chorioamnionitis was common in the BSCI and GBS groups, but was more severe in the BSCI+GBS group with greater myeloperoxidase staining (granulocyte marker) in the amnion and chorion ( < 0.05 vs. GBS). Collectively, these observations indicate that blocking the chemokine response to infection powerfully suppressed uterine contractility, PTL and the cytokine response, but did not prevent MIAC and fetal pneumonia. Development of PTL immunotherapies should occur in tandem with evaluation for AF microbes and consideration for antibiotic therapy.
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http://dx.doi.org/10.3389/fimmu.2020.00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203489PMC
March 2021

A Multisite Randomized Controlled Two-Phase Trial of the Early Start Denver Model Compared to Treatment as Usual.

J Am Acad Child Adolesc Psychiatry 2019 09 24;58(9):853-865. Epub 2019 Jan 24.

University of California, Davis, MIND Institute, Sacramento.

Objective: This single-blind, randomized, multisite, intent-to-treat study was designed to replicate and extend Dawson et al.'s (Pediatrics. 2010;125: e17-e23) randomized controlled trial testing the effects of the Early Start Denver Model (ESDM), an intensive play- and routines-based intervention delivered in natural settings.

Method: A randomized controlled trial was conducted at 3 universities. One hundred eighteen children 14 to 24 months old with autism spectrum disorder were enrolled and randomly assigned to ESDM or community interventions for 27 months. Eighty-one children completed the full treatment course and all assessments; data from all 118 children were used in analyses. Children assigned to the ESDM intervention received 3 months of weekly parent coaching followed by 24 months of 15 hour per week (on average) 1:1 treatment weekly on average in homes or daycare settings from supervised therapy assistants while parents received coaching 4 hours monthly from a certified ESDM therapist.

Results: For the primary analyses, there were time-by-group and time-by-group-by-site interactions for language outcome. In the significant 3-way interaction involving site, 2 sites showed a significant ESDM advantage and the third site showed no significant group differences. In the planned 2-way analysis that pooled data across all 3 sites, there was a significant advantage found for the ESDM group. For the secondary analyses, there were no significant differences between the ESDM and community groups involving developmental quotient, autism severity, or adaptive behavior. The treatment effect of group on language outcomes was not moderated by baseline developmental quotient, autism severity, or language.

Conclusion: Results of the primary analysis provide a partial replication of Dawson et al.'s 2010 language findings.

Clinical Trial Registration Information: Intensive Intervention for Toddlers with Autism; https://clinicaltrials.gov/; NCT00698997.
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http://dx.doi.org/10.1016/j.jaac.2019.01.004DOI Listing
September 2019

The Developmental Sequence and Relations Between Gesture and Spoken Language in Toddlers With Autism Spectrum Disorder.

Child Dev 2020 05 31;91(3):743-753. Epub 2018 Dec 31.

University of California, Davis.

In typical development, gestures precede and predict language development. This study examines the developmental sequence of expressive communication and relations between specific gestural and language milestones in toddlers with autism spectrum disorder (ASD), who demonstrate marked difficulty with gesture production and language. Communication skills across five stages (gestures, word approximations, first words, gesture-word combinations, and two-word combinations) were assessed monthly by blind raters for toddlers with ASD participating in an randomized control trial of parent-mediated treatment (N = 42, 12-30 months). Findings revealed that toddlers acquired skills following a reliable (vs. idiosyncratic) sequence and the majority of toddlers combined gestures with words before combining words in speech, but in contrast to the pattern observed in typical development, a significant subset acquired pointing after first words.
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http://dx.doi.org/10.1111/cdev.13203DOI Listing
May 2020

Cost Offset Associated With Early Start Denver Model for Children With Autism.

J Am Acad Child Adolesc Psychiatry 2017 Sep 4;56(9):777-783. Epub 2017 Jul 4.

Center for Mental Health Policy and Services Research, University of Pennsylvania Perelman School of Medicine and Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia.

Objective: To determine the effect of the Early Start Denver Model (ESDM) for treatment of young children with autism on health care service use and costs.

Method: We used data from a randomized trial that tested the efficacy of the ESDM, which is based on developmental and applied behavioral analytic principles and delivered by trained therapists and parents, for 2 years. Parents were interviewed about their children's service use every 6 months from the onset of the intervention to follow-up (age 6 years). The sample for this study consisted of 39 children with autism who participated in the original randomized trial at age 18 to 30 months, and were also assessed at age 6 years. Of this sample, 21 children were in the ESDM group, and 18 children were in the community care (COM) group. Reported services were categorized and costed by applying unit hourly costs. Annualized service use and costs during the intervention and post intervention for the two study arms were compared.

Results: During the intervention, children who received the ESDM had average annualized total health-related costs that were higher by about $14,000 than those of children who received community-based treatment. The higher cost of ESDM was partially offset during the intervention period because children in the ESDM group used less applied behavior analysis (ABA)/early intensive behavioral intervention (EIBI) and speech therapy services than children in the comparison group. In the postintervention period, compared with children who had earlier received treatment as usual in community settings, children in the ESDM group used less ABA/EIBI, occupational/physical therapy, and speech therapy services, resulting in significant cost savings in the amount of about $19,000 per year per child.

Conclusion: Costs associated with ESDM treatment were fully offset within a few years after the intervention because of reductions in other service use and associated costs.

Clinical Trial Registration Information: Early Characteristics of Autism; http://clinicaltrials.gov/; NCT0009415.
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http://dx.doi.org/10.1016/j.jaac.2017.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007927PMC
September 2017

The Relationship Between Early Neural Responses to Emotional Faces at Age 3 and Later Autism and Anxiety Symptoms in Adolescents with Autism.

J Autism Dev Disord 2016 Jul;46(7):2450-63

Center on Child Health, Behavior, and Development, Seattle Children's Research Institute, PO Box 5371, Seattle, WA, 98145, USA.

Both autism spectrum (ASD) and anxiety disorders are associated with atypical neural and attentional responses to emotional faces, differing in affective face processing from typically developing peers. Within a longitudinal study of children with ASD (23 male, 3 female), we hypothesized that early ERPs to emotional faces would predict concurrent and later ASD and anxiety symptoms. Greater response amplitude to fearful faces corresponded to greater social communication difficulties at age 3, and less improvement by age 14. Faster ERPs to neutral faces predicted greater ASD symptom improvement over time, lower ASD severity in adolescence, and lower anxiety in adolescence. Early individual differences in processing of emotional stimuli likely reflect a unique predictive contribution from social brain circuitry early in life.
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http://dx.doi.org/10.1007/s10803-016-2780-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305034PMC
July 2016

Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes.

Hum Genet 2015 Oct 24;134(10):1055-68. Epub 2015 Jul 24.

Division of Medical Genetics, School of Medicine, University of Washington, Seattle, WA, USA.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders, characterized by impairment in communication and social interactions, and by repetitive behaviors. ASDs are highly heritable, and estimates of the number of risk loci range from hundreds to >1000. We considered 7 extended families (size 12-47 individuals), each with ≥3 individuals affected by ASD. All individuals were genotyped with dense SNP panels. A small subset of each family was typed with whole exome sequence (WES). We used a 3-step approach for variant identification. First, we used family-specific parametric linkage analysis of the SNP data to identify regions of interest. Second, we filtered variants in these regions based on frequency and function, obtaining exactly 200 candidates. Third, we compared two approaches to narrowing this list further. We used information from the SNP data to impute exome variant dosages into those without WES. We regressed affected status on variant allele dosage, using pedigree-based kinship matrices to account for relationships. The p value for the test of the null hypothesis that variant allele dosage is unrelated to phenotype was used to indicate strength of evidence supporting the variant. A cutoff of p = 0.05 gave 28 variants. As an alternative third filter, we required Mendelian inheritance in those with WES, resulting in 70 variants. The imputation- and association-based approach was effective. We identified four strong candidate genes for ASD (SEZ6L, HISPPD1, FEZF1, SAMD11), all of which have been previously implicated in other studies, or have a strong biological argument for their relevance.
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http://dx.doi.org/10.1007/s00439-015-1585-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578871PMC
October 2015

Transmission disequilibrium of small CNVs in simplex autism.

Am J Hum Genet 2013 Oct 12;93(4):595-606. Epub 2013 Sep 12.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.

We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.
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http://dx.doi.org/10.1016/j.ajhg.2013.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791263PMC
October 2013

Atypical developmental patterns of brain chemistry in children with autism spectrum disorder.

JAMA Psychiatry 2013 Sep;70(9):964-74

Importance: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with symptoms emerging during early childhood. The pathophysiology underlying the disorder remains incompletely understood.

Objective: To examine cross-sectional and longitudinal patterns of brain chemical concentrations in children with ASD or idiopathic developmental delay (DD) from 3 different age points, beginning early in the clinical course.

Design: Proton magnetic resonance spectroscopic imaging data were acquired longitudinally for children with ASD or DD, and primarily cross-sectionally for children with typical development (TD), at 3 to 4, 6 to 7, and 9 to 10 years of age.

Setting: Recruitment, diagnostic assessments, and magnetic resonance imaging were performed at the University of Washington in Seattle.

Participants: Seventy-three children (45 with ASD, 14 with DD, and 14 with TD) at 3 to 4 years of age; 69 children (35 with ASD, 14 with DD, and 20 with TD) at 6 to 7 years of age; and 77 children (29 with ASD, 15 with DD, and 33 with TD) at 9 to 10 years of age.

Main Outcomes And Measures: Concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mI), and glutamine plus glutamate (Glx) in cerebral gray matter (GM) and white matter (WM) at 3 to 4, 6 to 7, and 9 to 10 years of age, and calculation of rates of change of these chemicals between 3 and 10 years of age.

Results: At 3 to 4 years of age, the ASD group exhibited lower NAA, Cho, and Cr concentrations than did the TD group in both GM and WM, alterations that largely were not observed at 9 to 10 years of age. The DD group exhibited reduced GM and WM NAA concentrations at 3 to 4 years of age; GM NAA concentrations remained reduced at 9 to 10 years of age compared with the TD group. There were distinct differences between the ASD and DD groups in the rates of GM NAA, Cho, and Cr changes between 3 and 10 years of age.

Conclusions And Relevance: The GM chemical changes between 3 and 10 years of age differentiated the children with ASD from those with DD. Most notably, a dynamic reversal of GM NAA reductions was observed in the children with ASD. By contrast, persistent GM NAA reductions in the children with DD suggest a different, more static, underlying developmental process.
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http://dx.doi.org/10.1001/jamapsychiatry.2013.1388DOI Listing
September 2013

Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.

Science 2012 Dec 15;338(6114):1619-22. Epub 2012 Nov 15.

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.

Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes-CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1-may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin-chromatin-remodeling network to ASD etiology.
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http://dx.doi.org/10.1126/science.1227764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528801PMC
December 2012

Individual common variants exert weak effects on the risk for autism spectrum disorders.

Authors:
Richard Anney Lambertus Klei Dalila Pinto Joana Almeida Elena Bacchelli Gillian Baird Nadia Bolshakova Sven Bölte Patrick F Bolton Thomas Bourgeron Sean Brennan Jessica Brian Jillian Casey Judith Conroy Catarina Correia Christina Corsello Emily L Crawford Maretha de Jonge Richard Delorme Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A Fernandez Susan E Folstein Eric Fombonne John Gilbert Christopher Gillberg Joseph T Glessner Andrew Green Jonathan Green Stephen J Guter Elizabeth A Heron Richard Holt Jennifer L Howe Gillian Hughes Vanessa Hus Roberta Igliozzi Suma Jacob Graham P Kenny Cecilia Kim Alexander Kolevzon Vlad Kustanovich Clara M Lajonchere Janine A Lamb Miriam Law-Smith Marion Leboyer Ann Le Couteur Bennett L Leventhal Xiao-Qing Liu Frances Lombard Catherine Lord Linda Lotspeich Sabata C Lund Tiago R Magalhaes Carine Mantoulan Christopher J McDougle Nadine M Melhem Alison Merikangas Nancy J Minshew Ghazala K Mirza Jeff Munson Carolyn Noakes Gudrun Nygren Katerina Papanikolaou Alistair T Pagnamenta Barbara Parrini Tara Paton Andrew Pickles David J Posey Fritz Poustka Jiannis Ragoussis Regina Regan Wendy Roberts Kathryn Roeder Bernadette Roge Michael L Rutter Sabine Schlitt Naisha Shah Val C Sheffield Latha Soorya Inês Sousa Vera Stoppioni Nuala Sykes Raffaella Tancredi Ann P Thompson Susanne Thomson Ana Tryfon John Tsiantis Herman Van Engeland John B Vincent Fred Volkmar J A S Vorstman Simon Wallace Kirsty Wing Kerstin Wittemeyer Shawn Wood Danielle Zurawiecki Lonnie Zwaigenbaum Anthony J Bailey Agatino Battaglia Rita M Cantor Hilary Coon Michael L Cuccaro Geraldine Dawson Sean Ennis Christine M Freitag Daniel H Geschwind Jonathan L Haines Sabine M Klauck William M McMahon Elena Maestrini Judith Miller Anthony P Monaco Stanley F Nelson John I Nurnberger Guiomar Oliveira Jeremy R Parr Margaret A Pericak-Vance Joseph Piven Gerard D Schellenberg Stephen W Scherer Astrid M Vicente Thomas H Wassink Ellen M Wijsman Catalina Betancur Joseph D Buxbaum Edwin H Cook Louise Gallagher Michael Gill Joachim Hallmayer Andrew D Paterson James S Sutcliffe Peter Szatmari Veronica J Vieland Hakon Hakonarson Bernie Devlin

Hum Mol Genet 2012 Nov 26;21(21):4781-92. Epub 2012 Jul 26.

Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
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http://dx.doi.org/10.1093/hmg/dds301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471395PMC
November 2012

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Authors:
Jillian P Casey Tiago Magalhaes Judith M Conroy Regina Regan Naisha Shah Richard Anney Denis C Shields Brett S Abrahams Joana Almeida Elena Bacchelli Anthony J Bailey Gillian Baird Agatino Battaglia Tom Berney Nadia Bolshakova Patrick F Bolton Thomas Bourgeron Sean Brennan Phil Cali Catarina Correia Christina Corsello Marc Coutanche Geraldine Dawson Maretha de Jonge Richard Delorme Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A Fernandez Susan E Folstein Suzanne Foley Eric Fombonne Christine M Freitag John Gilbert Christopher Gillberg Joseph T Glessner Jonathan Green Stephen J Guter Hakon Hakonarson Richard Holt Gillian Hughes Vanessa Hus Roberta Igliozzi Cecilia Kim Sabine M Klauck Alexander Kolevzon Janine A Lamb Marion Leboyer Ann Le Couteur Bennett L Leventhal Catherine Lord Sabata C Lund Elena Maestrini Carine Mantoulan Christian R Marshall Helen McConachie Christopher J McDougle Jane McGrath William M McMahon Alison Merikangas Judith Miller Fiorella Minopoli Ghazala K Mirza Jeff Munson Stanley F Nelson Gudrun Nygren Guiomar Oliveira Alistair T Pagnamenta Katerina Papanikolaou Jeremy R Parr Barbara Parrini Andrew Pickles Dalila Pinto Joseph Piven David J Posey Annemarie Poustka Fritz Poustka Jiannis Ragoussis Bernadette Roge Michael L Rutter Ana F Sequeira Latha Soorya Inês Sousa Nuala Sykes Vera Stoppioni Raffaella Tancredi Maïté Tauber Ann P Thompson Susanne Thomson John Tsiantis Herman Van Engeland John B Vincent Fred Volkmar Jacob A S Vorstman Simon Wallace Kai Wang Thomas H Wassink Kathy White Kirsty Wing Kerstin Wittemeyer Brian L Yaspan Lonnie Zwaigenbaum Catalina Betancur Joseph D Buxbaum Rita M Cantor Edwin H Cook Hilary Coon Michael L Cuccaro Daniel H Geschwind Jonathan L Haines Joachim Hallmayer Anthony P Monaco John I Nurnberger Margaret A Pericak-Vance Gerard D Schellenberg Stephen W Scherer James S Sutcliffe Peter Szatmari Veronica J Vieland Ellen M Wijsman Andrew Green Michael Gill Louise Gallagher Astrid Vicente Sean Ennis

Hum Genet 2012 Apr 14;131(4):565-79. Epub 2011 Oct 14.

School of Medicine and Medical Science University College, Dublin, Ireland.

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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http://dx.doi.org/10.1007/s00439-011-1094-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303079PMC
April 2012

Evidence for broader autism phenotype characteristics in parents from multiple-incidence autism families.

Autism Res 2012 Feb 8;5(1):13-20. Epub 2011 Sep 8.

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.

The broader autism phenotype (BAP) was assessed in parents who have two or more children with autism spectrum disorder (ASD) (multiplex (MPX) autism), parents who have no more than one child with ASD (simplex autism), parents who have a child with developmental delay without ASD, and parents who have typically developing children. Clinicians, naive to parent group membership status, rated BAP characteristics from videotaped administration of the Broader Autism Phenotype Symptom Scale (BPASS). Differences among groups in BPASS scores in the four assessed domains (social motivation, conversational skills, expressiveness, and restricted interests) were examined using multivariate ANOVA and post hoc comparisons. Further, ratings of videotapes by observers naïve to family status were compared with live, non-naive ratings by observers who were aware of family status (non-naïve). Findings demonstrate that the BPASS is an instrument resistant to rater bias. Parents from MPX autism families showed significantly more autism phenotype characteristics than the parents in the other groups. Moreover, the parents from simplex autism families did not differ from the parents of children with developmental delay or typical development. Finally, no differences between live, non-naive ratings and videotaped, naive ratings were observed. These findings suggest that characteristics of the BAP, specifically in the social and communication domains, are present in MPX autism parents to a greater degree than simplex autism and control parents. Further, the results provide support for the notion that genetic transmission mechanisms may differ between families with more than one child with autism and families with only one child with autism.
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http://dx.doi.org/10.1002/aur.226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237782PMC
February 2012

Genome-scan for IQ discrepancy in autism: evidence for loci on chromosomes 10 and 16.

Hum Genet 2011 Jan 21;129(1):59-70. Epub 2010 Oct 21.

Department of Medicine, University of Washington, Seattle, WA, USA.

Performance IQ (PIQ) greater than verbal IQ (VIQ) is often observed in studies of the cognitive abilities of autistic individuals. This characteristic is correlated with social and communication impairments, key parts of the autism diagnosis. We present the first genetic analyses of IQ discrepancy (PIQ-VIQ) as an autism-related phenotype. We performed genome-wide joint linkage and segregation analyses on 287 multiplex families, using a Markov chain Monte Carlo approach. Genetic data included a genome-scan of 387 micro-satellite markers in 210 families augmented with additional markers added in a subset of families. Empirical P values were calculated for five interesting regions. Linkage analysis identified five chromosomal regions with substantial regional evidence of linkage; 10p12 [P = 0.001; genome-wide (gw) P = 0.05], 16q23 (P = .015; gw P = 0.53), 2p21 (P = 0.03, gw P = 0.78), 6q25 (P = 0.047, gw P = 0.91) and 15q23-25 (P = 0.053, gw P = 0.93). The location of the chromosome 10 linkage signal coincides with a region noted in a much earlier genome-scan for autism, and the chromosome 16 signal coincides exactly with a linkage signal for non-word repetition in specific language impairment. This study provides strong evidence for a QTL influencing IQ discrepancy in families with autistic individuals on chromosome 10, and suggestive evidence for a QTL on chromosome 16. The location of the chromosome 16 signal suggests a candidate gene, CDH13, a T-cadherin expressed in the brain, which has been implicated in previous SNP studies of autism and ADHD.
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http://dx.doi.org/10.1007/s00439-010-0899-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082447PMC
January 2011

A genome-wide scan for common alleles affecting risk for autism.

Authors:
Richard Anney Lambertus Klei Dalila Pinto Regina Regan Judith Conroy Tiago R Magalhaes Catarina Correia Brett S Abrahams Nuala Sykes Alistair T Pagnamenta Joana Almeida Elena Bacchelli Anthony J Bailey Gillian Baird Agatino Battaglia Tom Berney Nadia Bolshakova Sven Bölte Patrick F Bolton Thomas Bourgeron Sean Brennan Jessica Brian Andrew R Carson Guillermo Casallo Jillian Casey Su H Chu Lynne Cochrane Christina Corsello Emily L Crawford Andrew Crossett Geraldine Dawson Maretha de Jonge Richard Delorme Irene Drmic Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A Fernandez Susan E Folstein Eric Fombonne Christine M Freitag John Gilbert Christopher Gillberg Joseph T Glessner Jeremy Goldberg Jonathan Green Stephen J Guter Hakon Hakonarson Elizabeth A Heron Matthew Hill Richard Holt Jennifer L Howe Gillian Hughes Vanessa Hus Roberta Igliozzi Cecilia Kim Sabine M Klauck Alexander Kolevzon Olena Korvatska Vlad Kustanovich Clara M Lajonchere Janine A Lamb Magdalena Laskawiec Marion Leboyer Ann Le Couteur Bennett L Leventhal Anath C Lionel Xiao-Qing Liu Catherine Lord Linda Lotspeich Sabata C Lund Elena Maestrini William Mahoney Carine Mantoulan Christian R Marshall Helen McConachie Christopher J McDougle Jane McGrath William M McMahon Nadine M Melhem Alison Merikangas Ohsuke Migita Nancy J Minshew Ghazala K Mirza Jeff Munson Stanley F Nelson Carolyn Noakes Abdul Noor Gudrun Nygren Guiomar Oliveira Katerina Papanikolaou Jeremy R Parr Barbara Parrini Tara Paton Andrew Pickles Joseph Piven David J Posey Annemarie Poustka Fritz Poustka Aparna Prasad Jiannis Ragoussis Katy Renshaw Jessica Rickaby Wendy Roberts Kathryn Roeder Bernadette Roge Michael L Rutter Laura J Bierut John P Rice Jeff Salt Katherine Sansom Daisuke Sato Ricardo Segurado Lili Senman Naisha Shah Val C Sheffield Latha Soorya Inês Sousa Vera Stoppioni Christina Strawbridge Raffaella Tancredi Katherine Tansey Bhooma Thiruvahindrapduram Ann P Thompson Susanne Thomson Ana Tryfon John Tsiantis Herman Van Engeland John B Vincent Fred Volkmar Simon Wallace Kai Wang Zhouzhi Wang Thomas H Wassink Kirsty Wing Kerstin Wittemeyer Shawn Wood Brian L Yaspan Danielle Zurawiecki Lonnie Zwaigenbaum Catalina Betancur Joseph D Buxbaum Rita M Cantor Edwin H Cook Hilary Coon Michael L Cuccaro Louise Gallagher Daniel H Geschwind Michael Gill Jonathan L Haines Judith Miller Anthony P Monaco John I Nurnberger Andrew D Paterson Margaret A Pericak-Vance Gerard D Schellenberg Stephen W Scherer James S Sutcliffe Peter Szatmari Astrid M Vicente Veronica J Vieland Ellen M Wijsman Bernie Devlin Sean Ennis Joachim Hallmayer

Hum Mol Genet 2010 Oct 27;19(20):4072-82. Epub 2010 Jul 27.

Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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http://dx.doi.org/10.1093/hmg/ddq307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947401PMC
October 2010

Functional impact of global rare copy number variation in autism spectrum disorders.

Authors:
Dalila Pinto Alistair T Pagnamenta Lambertus Klei Richard Anney Daniele Merico Regina Regan Judith Conroy Tiago R Magalhaes Catarina Correia Brett S Abrahams Joana Almeida Elena Bacchelli Gary D Bader Anthony J Bailey Gillian Baird Agatino Battaglia Tom Berney Nadia Bolshakova Sven Bölte Patrick F Bolton Thomas Bourgeron Sean Brennan Jessica Brian Susan E Bryson Andrew R Carson Guillermo Casallo Jillian Casey Brian H Y Chung Lynne Cochrane Christina Corsello Emily L Crawford Andrew Crossett Cheryl Cytrynbaum Geraldine Dawson Maretha de Jonge Richard Delorme Irene Drmic Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A Fernandez Susan E Folstein Eric Fombonne Christine M Freitag John Gilbert Christopher Gillberg Joseph T Glessner Jeremy Goldberg Andrew Green Jonathan Green Stephen J Guter Hakon Hakonarson Elizabeth A Heron Matthew Hill Richard Holt Jennifer L Howe Gillian Hughes Vanessa Hus Roberta Igliozzi Cecilia Kim Sabine M Klauck Alexander Kolevzon Olena Korvatska Vlad Kustanovich Clara M Lajonchere Janine A Lamb Magdalena Laskawiec Marion Leboyer Ann Le Couteur Bennett L Leventhal Anath C Lionel Xiao-Qing Liu Catherine Lord Linda Lotspeich Sabata C Lund Elena Maestrini William Mahoney Carine Mantoulan Christian R Marshall Helen McConachie Christopher J McDougle Jane McGrath William M McMahon Alison Merikangas Ohsuke Migita Nancy J Minshew Ghazala K Mirza Jeff Munson Stanley F Nelson Carolyn Noakes Abdul Noor Gudrun Nygren Guiomar Oliveira Katerina Papanikolaou Jeremy R Parr Barbara Parrini Tara Paton Andrew Pickles Marion Pilorge Joseph Piven Chris P Ponting David J Posey Annemarie Poustka Fritz Poustka Aparna Prasad Jiannis Ragoussis Katy Renshaw Jessica Rickaby Wendy Roberts Kathryn Roeder Bernadette Roge Michael L Rutter Laura J Bierut John P Rice Jeff Salt Katherine Sansom Daisuke Sato Ricardo Segurado Ana F Sequeira Lili Senman Naisha Shah Val C Sheffield Latha Soorya Inês Sousa Olaf Stein Nuala Sykes Vera Stoppioni Christina Strawbridge Raffaella Tancredi Katherine Tansey Bhooma Thiruvahindrapduram Ann P Thompson Susanne Thomson Ana Tryfon John Tsiantis Herman Van Engeland John B Vincent Fred Volkmar Simon Wallace Kai Wang Zhouzhi Wang Thomas H Wassink Caleb Webber Rosanna Weksberg Kirsty Wing Kerstin Wittemeyer Shawn Wood Jing Wu Brian L Yaspan Danielle Zurawiecki Lonnie Zwaigenbaum Joseph D Buxbaum Rita M Cantor Edwin H Cook Hilary Coon Michael L Cuccaro Bernie Devlin Sean Ennis Louise Gallagher Daniel H Geschwind Michael Gill Jonathan L Haines Joachim Hallmayer Judith Miller Anthony P Monaco John I Nurnberger Andrew D Paterson Margaret A Pericak-Vance Gerard D Schellenberg Peter Szatmari Astrid M Vicente Veronica J Vieland Ellen M Wijsman Stephen W Scherer James S Sutcliffe Catalina Betancur

Nature 2010 Jul 9;466(7304):368-72. Epub 2010 Jun 9.

The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
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http://dx.doi.org/10.1038/nature09146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021798PMC
July 2010

Head circumference as an early predictor of autism symptoms in younger siblings of children with autism spectrum disorder.

J Autism Dev Disord 2008 Jul 5;38(6):1104-11. Epub 2007 Dec 5.

Department of Psychology, Autism Center, University of Washington, Box 357920, Seattle, WA, USA.

Siblings of children with autism have an increased risk for autism spectrum disorders (ASD). As children with autism often exhibit an atypical trajectory of head circumference (HC) growth, HC may be an indicator of vulnerability to autism. This study investigated whether infant siblings of children with ASD (n = 77) with an atypical trajectory of HC growth were more likely than those without an atypical HC trajectory to develop autism symptoms. Results showed that infants who had larger HC at 12 months, and whose HC growth rate decelerated more rapidly between 12 and 24 months were more likely to exhibit autism symptoms than infants with more typical HC trajectories. Among infant siblings of children with autism, atypical HC growth might alert pediatricians to provide screening and/or referral for further evaluation.
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http://dx.doi.org/10.1007/s10803-007-0495-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612537PMC
July 2008

Rate of head circumference growth as a function of autism diagnosis and history of autistic regression.

J Child Neurol 2007 Oct;22(10):1182-90

Department of Psychiatry and Behavioral Sciences, University of Washington Autism Center, University of Washington, Seattle, WA 98195, USA.

Several reports indicate that autism spectrum disorder is associated with increased rate of head growth in early childhood. Increased rate of growth may index aberrant processes during early development, may precede the onset of symptoms, and may predict severity of the disease course. We examined rate of change in occipitofrontal circumference measurements (abstracted from medical records) in 28 boys with autism spectrum disorder and in 8 boys with developmental delay without autism from birth to age 36 months. Only children who had more than 3 occipitofrontal circumference measurements available during this age period were included. All data were converted to z scores based on the Centers for Disease Control and Prevention norms. Rate of growth from birth to age 36 months was statistically significantly higher for the autism spectrum disorder group than the developmental delay group, with children with autism spectrum disorder showing a statistically significant increase in occipitofrontal circumference relative to norms between 7 and 10 months; this group difference in rate of growth was more robust when height was used as a covariate. Rate of growth was not found to be different for children with autism spectrum disorder whose parents reported a history of loss of skills (regression) vs those whose parents reported early onset of autism symptoms. Findings from this study suggest that the aberrant growth is present in the first year of life and precedes the onset and diagnosis in children with autism spectrum disorder with and without a history of autistic regression.
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http://dx.doi.org/10.1177/0883073807306263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2977982PMC
October 2007

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Authors:
Peter Szatmari Andrew D Paterson Lonnie Zwaigenbaum Wendy Roberts Jessica Brian Xiao-Qing Liu John B Vincent Jennifer L Skaug Ann P Thompson Lili Senman Lars Feuk Cheng Qian Susan E Bryson Marshall B Jones Christian R Marshall Stephen W Scherer Veronica J Vieland Christopher Bartlett La Vonne Mangin Rhinda Goedken Alberto Segre Margaret A Pericak-Vance Michael L Cuccaro John R Gilbert Harry H Wright Ruth K Abramson Catalina Betancur Thomas Bourgeron Christopher Gillberg Marion Leboyer Joseph D Buxbaum Kenneth L Davis Eric Hollander Jeremy M Silverman Joachim Hallmayer Linda Lotspeich James S Sutcliffe Jonathan L Haines Susan E Folstein Joseph Piven Thomas H Wassink Val Sheffield Daniel H Geschwind Maja Bucan W Ted Brown Rita M Cantor John N Constantino T Conrad Gilliam Martha Herbert Clara Lajonchere David H Ledbetter Christa Lese-Martin Janet Miller Stan Nelson Carol A Samango-Sprouse Sarah Spence Matthew State Rudolph E Tanzi Hilary Coon Geraldine Dawson Bernie Devlin Annette Estes Pamela Flodman Lambertus Klei William M McMahon Nancy Minshew Jeff Munson Elena Korvatska Patricia M Rodier Gerard D Schellenberg Moyra Smith M Anne Spence Chris Stodgell Ping Guo Tepper Ellen M Wijsman Chang-En Yu Bernadette Rogé Carine Mantoulan Kerstin Wittemeyer Annemarie Poustka Bärbel Felder Sabine M Klauck Claudia Schuster Fritz Poustka Sven Bölte Sabine Feineis-Matthews Evelyn Herbrecht Gabi Schmötzer John Tsiantis Katerina Papanikolaou Elena Maestrini Elena Bacchelli Francesca Blasi Simona Carone Claudio Toma Herman Van Engeland Maretha de Jonge Chantal Kemner Frederieke Koop Frederike Koop Marjolein Langemeijer Marjolijn Langemeijer Channa Hijmans Channa Hijimans Wouter G Staal Gillian Baird Patrick F Bolton Michael L Rutter Emma Weisblatt Jonathan Green Catherine Aldred Julie-Anne Wilkinson Andrew Pickles Ann Le Couteur Tom Berney Helen McConachie Anthony J Bailey Kostas Francis Gemma Honeyman Aislinn Hutchinson Jeremy R Parr Simon Wallace Anthony P Monaco Gabrielle Barnby Kazuhiro Kobayashi Janine A Lamb Ines Sousa Nuala Sykes Edwin H Cook Stephen J Guter Bennett L Leventhal Jeff Salt Catherine Lord Christina Corsello Vanessa Hus Daniel E Weeks Fred Volkmar Maïté Tauber Eric Fombonne Andy Shih Kacie J Meyer

Nat Genet 2007 Mar 18;39(3):319-28. Epub 2007 Feb 18.

Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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http://dx.doi.org/10.1038/ng1985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867008PMC
March 2007

Rate of head growth decelerates and symptoms worsen in the second year of life in autism.

Biol Psychiatry 2007 Feb 29;61(4):458-64. Epub 2006 Nov 29.

Autism Center, University of Washington, Seattle, Washington, USA.

Background: Longitudinal studies of head circumference growth in infants later diagnosed with autism are needed to understand the accelerated head growth in this disorder.

Methods: We analyzed longitudinal head circumference data from birth to 3 years in 28 children later diagnosed with autism spectrum disorder on the basis of individual growth curve analyses using hierarchical linear models.

Results: Head circumference Z scores relative to norms significantly increased in the autism sample from birth to 12 months, but this pattern did not persist beyond 12 months. Rather, the rate of change in head circumference from 12 to 36 months was not different from the normative sample.

Conclusions: These results suggest that a period of exceptionally rapid head growth occurs during the first year of life in autism; after 12 months of age, the rate of head circumference growth decelerates relative to the rate during the first year of life. Studies of behavioral development in infants later diagnosed with autism suggest that the period of acceleration of head growth precedes and overlaps with the onset of behavioral symptoms, and the period of deceleration coincides with a period of worsening of symptoms in the second year of life.
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http://dx.doi.org/10.1016/j.biopsych.2006.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164865PMC
February 2007

Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism.

Am J Med Genet A 2006 Nov;140(21):2257-74

Department of Psychiatry, The Brain Institute at the University of Utah, Salt Lake City, Utah 84108, USA.

Data from 10 sites of the NICHD/NIDCD Collaborative Programs of Excellence in Autism were combined to study the distribution of head circumference and relationship to demographic and clinical variables. Three hundred thirty-eight probands with autism-spectrum disorder (ASD) including 208 probands with autism were studied along with 147 parents, 149 siblings, and typically developing controls. ASDs were diagnosed, and head circumference and clinical variables measured in a standardized manner across all sites. All subjects with autism met ADI-R, ADOS-G, DSM-IV, and ICD-10 criteria. The results show the distribution of standardized head circumference in autism is normal in shape, and the mean, variance, and rate of macrocephaly but not microcephaly are increased. Head circumference tends to be large relative to height in autism. No site, gender, age, SES, verbal, or non-verbal IQ effects were present in the autism sample. In addition to autism itself, standardized height and average parental head circumference were the most important factors predicting head circumference in individuals with autism. Mean standardized head circumference and rates of macrocephaly were similar in probands with autism and their parents. Increased head circumference was associated with a higher (more severe) ADI-R social algorithm score. Macrocephaly is associated with delayed onset of language. Although mean head circumference and rates of macrocephaly are increased in autism, a high degree of variability is present, underscoring the complex clinical heterogeneity of the disorder. The wide distribution of head circumference in autism has major implications for genetic, neuroimaging, and other neurobiological research.
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http://dx.doi.org/10.1002/ajmg.a.31465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899843PMC
November 2006

Early social attention impairments in autism: social orienting, joint attention, and attention to distress.

Dev Psychol 2004 Mar;40(2):271-83

Department of Psychology, Center on Human Development and Disability, University of Washington, Seattle, WA, USA.

This study investigated social attention impairments in autism (social orienting, joint attention, and attention to another's distress) and their relations to language ability. Three- to four-year-old children with autism spectrum disorder (ASD; n = 72), 3- to 4-year-old developmentally delayed children (n = 34), and 12- to 46-month-old typically developing children (n = 39), matched on mental age, were compared on measures of social orienting, joint attention, and attention to another's distress. Children with autism performed significantly worse than the comparison groups in all of these domains. Combined impairments in joint attention and social orienting were found to best distinguish young children with ASD from those without ASD. Structural equation modeling indicated that joint attention was the best predictor of concurrent language ability. Social orienting and attention to distress were indirectly related to language through their relations with joint attention. These results help to clarify the nature of social attention impairments in autism, offer clues to developmental mechanisms, and suggest targets for early intervention.
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http://dx.doi.org/10.1037/0012-1649.40.2.271DOI Listing
March 2004

Age-related differences in neural correlates of face recognition during the toddler and preschool years.

Dev Psychobiol 2003 Mar;42(2):148-59

Psychology Department, University of California, San Diego, La Jolla, CA 92093-0109, USA.

Research on the development of face recognition in infancy has shown that infants respond to faces as if they are special and recognize familiar faces early in development. Infants also show recognition and differential attachment to familiar people very early in development. We tested the hypothesis that infants' responses to familiar and unfamiliar faces differ at different ages. Specifically, we present data showing age-related changes in infants' brain responses to mother's face versus a stranger's face in children between 18 and 54 months of age. We propose that these changes are based on age-related differences in the perceived salience of the face of the primary caregiver versus strangers.
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http://dx.doi.org/10.1002/dev.10078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640993PMC
March 2003