Publications by authors named "Rachel Earl"

18 Publications

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SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

Authors:
Francesca Clementina Radio Kaifang Pang Andrea Ciolfi Michael A Levy Andrés Hernández-García Lucia Pedace Francesca Pantaleoni Zhandong Liu Elke de Boer Adam Jackson Alessandro Bruselles Haley McConkey Emilia Stellacci Stefania Lo Cicero Marialetizia Motta Rosalba Carrozzo Maria Lisa Dentici Kirsty McWalter Megha Desai Kristin G Monaghan Aida Telegrafi Christophe Philippe Antonio Vitobello Margaret Au Katheryn Grand Pedro A Sanchez-Lara Joanne Baez Kristin Lindstrom Peggy Kulch Jessica Sebastian Suneeta Madan-Khetarpal Chelsea Roadhouse Jennifer J MacKenzie Berrin Monteleone Carol J Saunders July K Jean Cuevas Laura Cross Dihong Zhou Taila Hartley Sarah L Sawyer Fabíola Paoli Monteiro Tania Vertemati Secches Fernando Kok Laura E Schultz-Rogers Erica L Macke Eva Morava Eric W Klee Jennifer Kemppainen Maria Iascone Angelo Selicorni Romano Tenconi David J Amor Lynn Pais Lyndon Gallacher Peter D Turnpenny Karen Stals Sian Ellard Sara Cabet Gaetan Lesca Joset Pascal Katharina Steindl Sarit Ravid Karin Weiss Alison M R Castle Melissa T Carter Louisa Kalsner Bert B A de Vries Bregje W van Bon Marijke R Wevers Rolph Pfundt Alexander P A Stegmann Bronwyn Kerr Helen M Kingston Kate E Chandler Willow Sheehan Abdallah F Elias Deepali N Shinde Meghan C Towne Nathaniel H Robin Dana Goodloe Adeline Vanderver Omar Sherbini Krista Bluske R Tanner Hagelstrom Caterina Zanus Flavio Faletra Luciana Musante Evangeline C Kurtz-Nelson Rachel K Earl Britt-Marie Anderlid Gilles Morin Marjon van Slegtenhorst Karin E M Diderich Alice S Brooks Joost Gribnau Ruben G Boers Teresa Robert Finestra Lauren B Carter Anita Rauch Paolo Gasparini Kym M Boycott Tahsin Stefan Barakat John M Graham Laurence Faivre Siddharth Banka Tianyun Wang Evan E Eichler Manuela Priolo Bruno Dallapiccola Lisenka E L M Vissers Bekim Sadikovic Daryl A Scott Jimmy Lloyd Holder Marco Tartaglia

Am J Hum Genet 2021 Feb 9. Epub 2021 Feb 9.

Genetics and Rare Disease Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address:

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.015DOI Listing
February 2021

Persistent occiput posterior position outcomes following manual rotation: a randomized controlled trial.

Am J Obstet Gynecol MFM 2021 Jan 6;3(2):100306. Epub 2021 Jan 6.

Sydney Institute for Women, Children and their Families, Sydney Local Health District, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney School of Public Health, Sydney, New South Wales, Australia.

Background: Persistent occiput posterior position in labor is associated with adverse maternal and perinatal outcomes. Prophylactic manual rotation from the occiput posterior position to the occiput anterior position in the second stage of labor is considered a safe and easy to perform procedure that in observational studies has shown promise as a method for preventing operative deliveries.

Objective: This study aimed to determine the efficacy of prophylactic manual rotation in the management of occiput posterior position for preventing operative delivery. The hypothesis was that among women who are at least 37 weeks pregnant and whose baby is in the occiput posterior position early in the second stage of labor, manual rotation will reduce the rate of operative delivery compared with the "sham" rotation.

Study Design: A double-blinded, parallel, superiority, multicenter, randomized controlled clinical trial in 4 tertiary hospitals was conducted in Australia. A total of 254 nulliparous and parous women with a term pregnancy and a baby in the occiput posterior position in the second stage of labor were randomly assigned to receive either a prophylactic manual rotation (n=127) or a sham rotation (n=127). The primary outcome was operative delivery (cesarean, forceps, or vacuum delivery). Secondary outcomes were cesarean delivery, combined maternal mortality and serious morbidity, and combined perinatal mortality and serious morbidity. Analysis was by intention to treat. Proportions were compared using chi-square tests adjusted for stratification variables using the Mantel-Haenszel method or the Fisher exact test. Planned subgroup analyses by operator experience and by manual rotation technique (digital or whole-hand rotation) were performed.

Results: Operative delivery occurred in 79 of 127 women (62%) assigned to prophylactic manual rotation and 90 of 127 women (71%) assigned to sham rotation (common risk difference, 12; 95% confidence interval, -1.7 to 26; P=.09). Among more experienced operators or investigators, operative delivery occurred in 46 of 74 women (62%) assigned to manual rotation and 52 of 71 women (73%) assigned to a sham rotation (common risk difference, 18; 95% confidence interval, -0.5 to 36; P=.07). Cesarean delivery occurred in 22 of 127 women (17%) in both groups. Instrumental delivery (forceps or vacuum) occurred in 57 of 127 women (45%) assigned to prophylactic manual rotation and 68 of 127 women (54%) assigned to sham rotation (common risk difference, 10; 95% confidence interval, -3.1 to 22; P=.14). There was no significant difference in the combined maternal and perinatal outcomes.

Conclusion: Prophylactic manual rotation did not result in a reduction in the rate of operative delivery. Given manual rotation was associated with a nonsignificant reduction in operative delivery, more randomized trials are needed, as our trial might have been underpowered. In addition, further research is required to further explore the potential impact of operator or investigator experience.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100306DOI Listing
January 2021

Brief Report: Associations Between Self-injurious Behaviors and Abdominal Pain Among Individuals with ASD-Associated Disruptive Mutations.

J Autism Dev Disord 2020 Nov 11. Epub 2020 Nov 11.

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

Self-injurious behaviors (SIB) are elevated in autism spectrum disorder (ASD) and related genetic disorders, but the genetic and biological mechanisms that contribute to SIB in ASD are poorly understood. This study examined rates and predictors of SIB in 112 individuals with disruptive mutations to ASD-risk genes. Current SIB were reported in 30% of participants and associated with poorer cognitive and adaptive skills. History of severe abdominal pain predicted higher rates of SIB and SIB severity after controlling for age and adaptive behavior; individuals with a history of severe abdominal pain were eight times more likely to exhibit SIB than those with no history. Future research is needed to examine associations between genetic risk, pain, and SIB in this population.
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http://dx.doi.org/10.1007/s10803-020-04774-zDOI Listing
November 2020

Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Nat Commun 2020 Oct 21;11(1):5398. Epub 2020 Oct 21.

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-19289-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578800PMC
October 2020

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Nat Commun 2020 10 1;11(1):4932. Epub 2020 Oct 1.

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
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http://dx.doi.org/10.1038/s41467-020-18723-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530681PMC
October 2020

The Autism Biomarkers Consortium for Clinical Trials (ABC-CT): Scientific Context, Study Design, and Progress Toward Biomarker Qualification.

Front Integr Neurosci 2020 9;14:16. Epub 2020 Apr 9.

Center for Child Health, Behavior and Development, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States.

Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA's Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD.
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http://dx.doi.org/10.3389/fnint.2020.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173348PMC
April 2020

Trauma and Autism Spectrum Disorder: Review, Proposed Treatment Adaptations and Future Directions.

J Child Adolesc Trauma 2019 Dec 10;12(4):529-547. Epub 2019 Apr 10.

Department of Psychiatry & Behavioral Sciences, University of Washington, ,

Empirical investigations of trauma and post-traumatic stress disorder (PTSD) in individuals with autism spectrum disorder (ASD) are lacking despite indications of increased risk for exposure to potentially traumatic events in this population. Research on the treatment of traumatic stress psychopathology in ASD is even more limited and suggests a critical need for guidance in the area of ASD-specific treatment adaptations. The current paper provides preliminary recommendations for adapting current evidenced-based, trauma-specific interventions, specifically trauma-focused cognitive behavioral therapy (TF-CBT), for individuals with ASD based on well-established and evidence-based practices for working with this population. These adaptations highlight the need to incorporate treatment goals related to ASD core symptoms and associated characteristics during treatment targeting traumatic stress symptoms. Future directions are discussed, including the development of instruments measuring trauma reactions in ASD, empirical investigations of modified trauma interventions for children with ASD to evaluate effectiveness, and collaboration between professionals specializing in ASD and trauma/PTSD to advance research and facilitate effective care for this community.
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http://dx.doi.org/10.1007/s40653-019-00253-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901292PMC
December 2019

The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals.

Am J Hum Genet 2019 11 24;105(5):947-958. Epub 2019 Oct 24.

Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland.

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e-7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2 and Bola2 animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849090PMC
November 2019

Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Authors:
Pleuntje J van der Sluijs Sandra Jansen Samantha A Vergano Miho Adachi-Fukuda Yasemin Alanay Adila AlKindy Anwar Baban Allan Bayat Stefanie Beck-Wödl Katherine Berry Emilia K Bijlsma Levinus A Bok Alwin F J Brouwer Ineke van der Burgt Philippe M Campeau Natalie Canham Krystyna Chrzanowska Yoyo W Y Chu Brain H Y Chung Karin Dahan Marjan De Rademaeker Anne Destree Tracy Dudding-Byth Rachel Earl Nursel Elcioglu Ellen R Elias Christina Fagerberg Alice Gardham Blanca Gener Erica H Gerkes Ute Grasshoff Arie van Haeringen Karin R Heitink Johanna C Herkert Nicolette S den Hollander Denise Horn David Hunt Sarina G Kant Mitsuhiro Kato Hülya Kayserili Rogier Kersseboom Esra Kilic Malgorzata Krajewska-Walasek Kylin Lammers Lone W Laulund Damien Lederer Melissa Lees Vanesa López-González Saskia Maas Grazia M S Mancini Carlo Marcelis Francisco Martinez Isabelle Maystadt Marianne McGuire Shane McKee Sarju Mehta Kay Metcalfe Jeff Milunsky Seiji Mizuno John B Moeschler Christian Netzer Charlotte W Ockeloen Barbara Oehl-Jaschkowitz Nobuhiko Okamoto Sharon N M Olminkhof Carmen Orellana Laurent Pasquier Caroline Pottinger Vera Riehmer Stephen P Robertson Maian Roifman Caroline Rooryck Fabienne G Ropers Monica Rosello Claudia A L Ruivenkamp Mahmut S Sagiroglu Suzanne C E H Sallevelt Amparo Sanchis Calvo Pelin O Simsek-Kiper Gabriela Soares Lucia Solaeche Fatma Mujgan Sonmez Miranda Splitt Duco Steenbeek Alexander P A Stegmann Constance T R M Stumpel Saori Tanabe Eyyup Uctepe G Eda Utine Hermine E Veenstra-Knol Sunita Venkateswaran Catheline Vilain Catherine Vincent-Delorme Anneke T Vulto-van Silfhout Patricia Wheeler Golder N Wilson Louise C Wilson Bernd Wollnik Tomoki Kosho Dagmar Wieczorek Evan Eichler Rolph Pfundt Bert B A de Vries Jill Clayton-Smith Gijs W E Santen

Genet Med 2019 Sep;21(9):2160-2161

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0368-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752317PMC
September 2019

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Authors:
Pleuntje J van der Sluijs Sandra Jansen Samantha A Vergano Miho Adachi-Fukuda Yasemin Alanay Adila AlKindy Anwar Baban Allan Bayat Stefanie Beck-Wödl Katherine Berry Emilia K Bijlsma Levinus A Bok Alwin F J Brouwer Ineke van der Burgt Philippe M Campeau Natalie Canham Krystyna Chrzanowska Yoyo W Y Chu Brain H Y Chung Karin Dahan Marjan De Rademaeker Anne Destree Tracy Dudding-Byth Rachel Earl Nursel Elcioglu Ellen R Elias Christina Fagerberg Alice Gardham Blanca Gener Erica H Gerkes Ute Grasshoff Arie van Haeringen Karin R Heitink Johanna C Herkert Nicolette S den Hollander Denise Horn David Hunt Sarina G Kant Mitsuhiro Kato Hülya Kayserili Rogier Kersseboom Esra Kilic Malgorzata Krajewska-Walasek Kylin Lammers Lone W Laulund Damien Lederer Melissa Lees Vanesa López-González Saskia Maas Grazia M S Mancini Carlo Marcelis Francisco Martinez Isabelle Maystadt Marianne McGuire Shane McKee Sarju Mehta Kay Metcalfe Jeff Milunsky Seiji Mizuno John B Moeschler Christian Netzer Charlotte W Ockeloen Barbara Oehl-Jaschkowitz Nobuhiko Okamoto Sharon N M Olminkhof Carmen Orellana Laurent Pasquier Caroline Pottinger Vera Riehmer Stephen P Robertson Maian Roifman Caroline Rooryck Fabienne G Ropers Monica Rosello Claudia A L Ruivenkamp Mahmut S Sagiroglu Suzanne C E H Sallevelt Amparo Sanchis Calvo Pelin O Simsek-Kiper Gabriela Soares Lucia Solaeche Fatma Mujgan Sonmez Miranda Splitt Duco Steenbeek Alexander P A Stegmann Constance T R M Stumpel Saori Tanabe Eyyup Uctepe G Eda Utine Hermine E Veenstra-Knol Sunita Venkateswaran Catheline Vilain Catherine Vincent-Delorme Anneke T Vulto-van Silfhout Patricia Wheeler Golder N Wilson Louise C Wilson Bernd Wollnik Tomoki Kosho Dagmar Wieczorek Evan Eichler Rolph Pfundt Bert B A de Vries Jill Clayton-Smith Gijs W E Santen

Genet Med 2019 06 8;21(6):1295-1307. Epub 2018 Nov 8.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.

Methods: Clinicians entered clinical data in an extensive web-based survey.

Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.

Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
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http://dx.doi.org/10.1038/s41436-018-0330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752273PMC
June 2019

Clinical phenotype of ASD-associated haploinsufficiency.

Mol Autism 2017 5;8:54. Epub 2017 Oct 5.

Department of Psychiatry and Behavioral Sciences, University of Washington, CHDD Box 357920, Seattle, WA 98195 USA.

Background: is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms.

Methods: Phenotypic information from previously published cases ( = 51) and participants in an ongoing study at the University of Washington (UW,  = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection ( = 1981). UW cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender ( = 10) and to cases with an ASD-associated disruptive mutation to ( = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW cases to their unaffected parents.

Results: haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype.

Conclusions: Results confirm a core clinical phenotype for disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with mutations are also distinguishable from disruptive mutations to by head size. Measurable, quantitative characterization of haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background.
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http://dx.doi.org/10.1186/s13229-017-0173-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629761PMC
February 2018

Developmental trajectories for young children with 16p11.2 copy number variation.

Am J Med Genet B Neuropsychiatr Genet 2017 Jun 27;174(4):367-380. Epub 2017 Mar 27.

Department of Pediatrics and Medicine, Columbia University, New York, New York.

Copy number variation at 16p11.2 is associated with diverse phenotypes but little is known about the early developmental trajectories and emergence of the phenotype. This longitudinal study followed 56 children with the 16p11.2 BP4-BP5 deletion or duplication between the ages of 6 months and 8 years with diagnostic characterization and dimensional assessment across cognitive, adaptive, and behavioral domains. Linear mixed modeling revealed distinct developmental trajectories with deletions showing VIQ gains but declines in motor and social abilities while duplications showed VIQ gains and steady development across other domains. Nonparametric analyses suggest distinct trajectories and early cognitive abilities for deletion carriers who are ultimately diagnosed with intellectual disability and developmental coordination disorder as well as distinct trajectories and early social communication and cognitive abilities for duplication carriers diagnosed with ASD and intellectual disability. Findings provide predictions for patient developmental trajectories, insight into mean functioning of individuals with 16p11.2 at early ages, and highlight the need for ongoing monitoring of social and motor functioning and behavioral symptomatology to improve treatment planning. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.b.32525DOI Listing
June 2017

Infant social attention: an endophenotype of ASD-related traits?

J Child Psychol Psychiatry 2017 03 8;58(3):270-281. Epub 2016 Nov 8.

Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, USA.

Background: As a neurodevelopmental disorder, symptoms of ASD likely emerge from a complex interaction between preexisting genetic vulnerabilities and the child's environment. One way to understand causal paths to ASD is to identify dimensional ASD-related traits that vary in the general population and that predispose individuals with other risk factors toward ASD. Moving beyond behavioral traits to explore underlying neurocognitive processes may further constrain the underlying genetics. Endophenotypes are quantitative, heritable, trait-related differences that are generally assessed with laboratory-based methods, can be identified in the general population, and may be more closely tied to particular causal chains that have a more restricted set of genetic roots. The most fruitful endophenotypes may be those observed in infancy, prior to the emergence of behavioral symptoms that they are hypothesized to cause. Social motivation is an ASD-related trait that is highly heritable. In this study, we investigate whether infant endophenotypes of social attention relate to familial risk for lower social motivation in the general population.

Methods: We examined whether infant social attention (measured using habituation, EEG power, and event-related potential tasks previously used in infants/toddlers with ASD) varies quantitatively with parental social motivation in 117 six-month-old and 106 twelve-month-old typically developing infants assessed cross-sectionally. To assess heritable aspects of social motivation, primary caregiver biological parents completed two self-report measures of social avoidance and discomfort that have shown high heritability in previous work.

Results: Parents with higher social discomfort and avoidance had infants who showed shorter looks to faces but not objects; reduced theta power during naturalistic social attention; and smaller P400 responses to faces versus objects.

Conclusions: Early reductions in social attention are continuously related to lower parental social motivation. Alterations in social attention may be infant endophenotypes of social motivation traits related to ASD.
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http://dx.doi.org/10.1111/jcpp.12650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993542PMC
March 2017

Developmental changes in infant brain activity during naturalistic social experiences.

Dev Psychobiol 2015 Nov 29;57(7):842-53. Epub 2015 Jul 29.

Center on Human Development and Disabilities, University of Washington, Seattle, WA.

Between 6 and 12 months, typically developing infants undergo a socio-cognitive "revolution." The Interactive Specialization (IS) theory of brain development predicts that these behavioral changes will be underpinned by developmental increases in the power and topographic extent of socially selective cortical responses. To test this hypothesis, we used EEG to examine developmental changes in cortical selectivity for ecologically valid dynamic social versus non-social stimuli in a large cohort of 6- and 12-month-old infants. Consistent with the Interactive Specialization model, results showed that differences in EEG Θ activity between social and non-social stimuli became more pronounced and widespread with age. Differences in EEG activity were most clearly elicited by a live naturalistic interaction, suggesting that measuring brain activity in ecologically valid contexts is central to mapping social brain development in infancy.
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http://dx.doi.org/10.1002/dev.21336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615531PMC
November 2015

Clinical phenotype of the recurrent 1q21.1 copy-number variant.

Genet Med 2016 Apr 11;18(4):341-9. Epub 2015 Jun 11.

Department of Pediatrics, Columbia University, New York, New York, USA.

Purpose: To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains.

Methods: Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging.

Results: Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers.

Conclusions: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.Genet Med 18 4, 341-349.
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http://dx.doi.org/10.1038/gim.2015.78DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263044PMC
April 2016

The promise of multi-omics and clinical data integration to identify and target personalized healthcare approaches in autism spectrum disorders.

OMICS 2015 Apr;19(4):197-208

1 Bioinformatics and High-Throughput Analysis Laboratory, Seattle Children's Research Institute , Seattle, Washington.

Complex diseases are caused by a combination of genetic and environmental factors, creating a difficult challenge for diagnosis and defining subtypes. This review article describes how distinct disease subtypes can be identified through integration and analysis of clinical and multi-omics data. A broad shift toward molecular subtyping of disease using genetic and omics data has yielded successful results in cancer and other complex diseases. To determine molecular subtypes, patients are first classified by applying clustering methods to different types of omics data, then these results are integrated with clinical data to characterize distinct disease subtypes. An example of this molecular-data-first approach is in research on Autism Spectrum Disorder (ASD), a spectrum of social communication disorders marked by tremendous etiological and phenotypic heterogeneity. In the case of ASD, omics data such as exome sequences and gene and protein expression data are combined with clinical data such as psychometric testing and imaging to enable subtype identification. Novel ASD subtypes have been proposed, such as CHD8, using this molecular subtyping approach. Broader use of molecular subtyping in complex disease research is impeded by data heterogeneity, diversity of standards, and ineffective analysis tools. The future of molecular subtyping for ASD and other complex diseases calls for an integrated resource to identify disease mechanisms, classify new patients, and inform effective treatment options. This in turn will empower and accelerate precision medicine and personalized healthcare.
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http://dx.doi.org/10.1089/omi.2015.0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389910PMC
April 2015

Interventions for hyperthyroidism pre-pregnancy and during pregnancy.

Cochrane Database Syst Rev 2013 Nov 19(11):CD008633. Epub 2013 Nov 19.

Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, The University of Adelaide, Medical School North Building, Frome Road, Adelaide, Australia, 5005.

Background: Women with hyperthyroidism in pregnancy have increased risks of miscarriage, stillbirth, preterm birth, and intrauterine growth restriction; and they can develop severe pre-eclampsia or placental abruption.

Objectives: To identify interventions used in the management of hyperthyroidism pre-pregnancy or during pregnancy and to ascertain the impact of these interventions on important maternal, fetal, neonatal and childhood outcomes.

Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2013).

Selection Criteria: We planned to include randomised controlled trials, quasi-randomised controlled trials, and cluster-randomised trials comparing antithyroid interventions for hyperthyroidism pre-pregnancy or during pregnancy with another intervention or no intervention (placebo or no treatment).

Data Collection And Analysis: Two review authors assessed trial eligibility and planned to assess trial quality and extract the data independently.

Main Results: No trials were included in the review.

Authors' Conclusions: As we did not identify any eligible trials, we are unable to comment on implications for practice, although early identification of hyperthyroidism before pregnancy may allow a woman to choose radioactive iodine therapy or surgery before planning to have a child. Designing and conducting a trial of antithyroid interventions for pregnant women with hyperthyroidism presents formidable challenges. Not only is hyperthyroidism a relatively rare condition, both of the two main drugs used have potential for harm, one for the mother and the other for the child. More observational research is required about the potential harms of methimazole in early pregnancy and about the potential liver damage from propylthiouracil.
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http://dx.doi.org/10.1002/14651858.CD008633.pub3DOI Listing
November 2013

Interventions for preventing and treating hyperthyroidism in pregnancy.

Cochrane Database Syst Rev 2010 Sep 8(9):CD008633. Epub 2010 Sep 8.

Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, The University of Adelaide, Medical School North Building, Frome Road, Adelaide, Australia, 5005.

Background: Women with hyperthyroidism in pregnancy have increased risks of miscarriage, stillbirth, preterm birth, and intrauterine growth restriction; and they can develop severe pre-eclampsia or placental abruption.

Objectives: To assess the effects of interventions for preventing or treating hyperthyroidism in pregnant women.

Search Strategy: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 July 2010).

Selection Criteria: We intended to include randomised controlled trials comparing antithyroid treatments in pregnant women with hyperthyroidism.

Data Collection And Analysis: Two review authors would have assessed trial eligibility and risk of bias, and extracted data.

Main Results: No trials were located.

Authors' Conclusions: As we did not identify any eligible trials, we are unable to comment on implications for practice, although early identification of hyperthyroidism before pregnancy may allow a woman to choose radioactive iodine therapy or surgery before planning to have a child. Designing and conducting a trial of antithyroid drugs for pregnant women with hyperthyroidism presents formidable challenges. Not only is hyperthyroidism a relatively rare condition, both of the two main drugs used have potential for harm, one for the mother and the other for the child. More observational research is required about the potential harms of methimazole in early pregnancy and about the potential liver damage from propylthiouracil.
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http://dx.doi.org/10.1002/14651858.CD008633.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175534PMC
September 2010