10 results on '"Marco, EJ."'
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2. Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome.
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Steele JL, Morrow MM, Sarnat HB, Alkhunaizi E, Brandt T, Chitayat DA, DeFilippo CP, Douglas GV, Dubbs HA, Elloumi HZ, Glassford MR, Hannibal MC, Héron B, Kim LE, Marco EJ, Mignot C, Monaghan KG, Myers KA, Parikh S, Quinonez SC, Rajabi F, Shankar SP, Shinawi MS, van de Kamp JJP, Veerapandiyan A, Waldman AT, and Graf WD
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- Adolescent, Adult, Autism Spectrum Disorder physiopathology, Child, Child, Preschool, Genetic Association Studies, Humans, Intellectual Disability physiopathology, Male, Signal Transduction physiology, Young Adult, Autism Spectrum Disorder genetics, Cell Adhesion Molecules physiology, Intellectual Disability genetics, Nerve Tissue Proteins physiology, Receptors, Cell Surface genetics, Semaphorins physiology
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Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants., Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant., Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05)., Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2022
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3. Brief Report: Pilot Study of a Novel Interactive Digital Treatment to Improve Cognitive Control in Children with Autism Spectrum Disorder and Co-occurring ADHD Symptoms.
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Yerys BE, Bertollo JR, Kenworthy L, Dawson G, Marco EJ, Schultz RT, and Sikich L
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- Adolescent, Attention Deficit Disorder with Hyperactivity epidemiology, Autism Spectrum Disorder epidemiology, Child, Comorbidity, Female, Humans, Male, Mobile Applications, Parents, Pilot Projects, Research Report, Therapy, Computer-Assisted instrumentation, Treatment Outcome, Attention Deficit Disorder with Hyperactivity psychology, Attention Deficit Disorder with Hyperactivity therapy, Autism Spectrum Disorder psychology, Autism Spectrum Disorder therapy, Cognition physiology, Therapy, Computer-Assisted methods
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The presence of attention deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD) is associated with worse cognitive control. Children with ASD and ADHD often respond poorly to medications, thus we need alternative treatments. We examined the feasibility, acceptability, and preliminary efficacy of Project Evo-a digital treatment. Nineteen children with ASD and co-occurring ADHD symptoms completed this app-based treatment that targets multi-tasking through gameplay versus a comparison educational treatment. Children had a high engagement with both treatments, and parents and children reported high acceptability. Within-group analyses suggest the multi-tasking but not the educational treatment may improve cognitive control. This multi-tasking treatment is feasible, acceptable, and possibly efficacious for cognitive control impairments in children with ASD and ADHD.
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- 2019
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4. White Matter Connectome Edge Density in Children with Autism Spectrum Disorders: Potential Imaging Biomarkers Using Machine-Learning Models.
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Payabvash S, Palacios EM, Owen JP, Wang MB, Tavassoli T, Gerdes M, Brandes-Aitken A, Cuneo D, Marco EJ, and Mukherjee P
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- Algorithms, Anisotropy, Autism Spectrum Disorder physiopathology, Bayes Theorem, Biomarkers, Brain diagnostic imaging, Brain physiopathology, Child, Computer Simulation, Diffusion Tensor Imaging methods, Humans, Machine Learning, Magnetic Resonance Imaging methods, Male, Neuroimaging methods, Sensitivity and Specificity, Support Vector Machine, White Matter physiopathology, Autism Spectrum Disorder diagnostic imaging, Connectome methods, White Matter diagnostic imaging
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Prior neuroimaging studies have reported white matter network underconnectivity as a potential mechanism for autism spectrum disorder (ASD). In this study, we examined the structural connectome of children with ASD using edge density imaging (EDI), and then applied machine-learning algorithms to identify children with ASD based on tract-based connectivity metrics. Boys aged 8-12 years were included: 14 with ASD and 33 typically developing children. The edge density (ED) maps were computed from probabilistic streamline tractography applied to high angular resolution diffusion imaging. Tract-based spatial statistics was used for voxel-wise comparison and coregistration of ED maps in addition to conventional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Tract-based average DTI/connectome metrics were calculated and used as input for different machine-learning models: naïve Bayes, random forest, support vector machines (SVMs), and neural networks. For these models, cross-validation was performed with stratified random sampling ( × 1,000 permutations). The average accuracy among validation samples was calculated. In voxel-wise analysis, the body and splenium of corpus callosum, bilateral superior and posterior corona radiata, and left superior longitudinal fasciculus showed significantly lower ED in children with ASD; whereas, we could not find significant difference in FA, MD, and RD maps between the two study groups. Overall, machine-learning models using tract-based ED metrics had better performance in identification of children with ASD compared with those using FA, MD, and RD. The EDI-based random forest models had greater average accuracy (75.3%), specificity (97.0%), and positive predictive value (81.5%), whereas EDI-based polynomial SVM had greater sensitivity (51.4%) and negative predictive values (77.7%). In conclusion, we found reduced density of connectome edges in the posterior white matter tracts of children with ASD, and demonstrated the feasibility of connectome-based machine-learning algorithms in identification of children with ASD.
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- 2019
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5. Burden of de novo mutations and inherited rare single nucleotide variants in children with sensory processing dysfunction.
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Marco EJ, Aitken AB, Nair VP, da Gente G, Gerdes MR, Bologlu L, Thomas S, and Sherr EH
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- Autism Spectrum Disorder psychology, Child, Cohort Studies, Exome genetics, Female, Genetic Predisposition to Disease genetics, Humans, Male, Parents, Siblings, Autism Spectrum Disorder genetics, Autism Spectrum Disorder physiopathology, Mutation, Sensation genetics
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Background: In children with sensory processing dysfunction (SPD), who do not meet criteria for autism spectrum disorder (ASD) or intellectual disability, the contribution of de novo pathogenic mutation in neurodevelopmental genes is unknown and in need of investigation. We hypothesize that children with SPD may have pathogenic variants in genes that have been identified as causing other neurodevelopmental disorders including ASD. This genetic information may provide important insight into the etiology of sensory processing dysfunction and guide clinical evaluation and care., Methods: Eleven community-recruited trios (children with isolated SPD and both biological parents) underwent WES to identify candidate de novo variants and inherited rare single nucleotide variants (rSNV) in genes previously associated with ASD. Gene enrichment in these children and their parents for transmitted and non-transmitted mutation burden was calculated. A comparison analysis to assess for enriched rSNV burden was then performed in 2377 children with ASD and their families from the Simons Simplex Collection., Results: Of the children with SPD, 2/11 (18%), were identified as having a de novo loss of function or missense mutation in genes previously reported as causative for neurodevelopmental disorders (MBD5 and FMN2). We also found that the parents of children with SPD have significant enrichment of pathogenic rSNV burden in high-risk ASD candidate genes that are inherited by their affected children. Using the same approach, we confirmed enrichment of rSNV burden in a large cohort of children with autism and their parents but not unaffected siblings., Conclusions: Our findings suggest that SPD, like autism, has a genetic basis that includes both de novo single gene mutations as well as an accumulated burden of rare inherited variants from their parents.
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- 2018
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6. Characterizing cognitive and visuomotor control in children with sensory processing dysfunction and autism spectrum disorders.
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Brandes-Aitken A, Anguera JA, Rolle CE, Desai SS, Demopoulos C, Skinner SN, Gazzaley A, and Marco EJ
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- Attention, Child, Discrimination, Psychological, Female, Humans, Male, Reaction Time, Autism Spectrum Disorder psychology, Cognition, Psychomotor Performance, Sensation Disorders psychology
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Objective: Children with autism spectrum disorders (ASD) and sensory processing dysfunction (SPD) are reported to show difficulties involving cognitive and visuomotor control. We sought to determine whether performance on computerized, behavioral measures of cognitive control aimed at assessing selective attention, as well as visuomotor abilities differentiated children with ASD (n = 14), SPD (n = 14) and typically developing controls (TDC; n = 28)., Method: Cognitive control differences were measured by assessing selective attention-based abilities both with and without distracting stimuli, and visuomotor differences were measured by characterizing visuomotor tracking and tracing skills. Performance in cognitive control and visuomotor domains were investigated globally as composite scores, and specifically within each task., Results: Our results indicated that though the ASD group showed the most impaired selective attention performance, the SPD group had intermediate abilities-performing above the ASD group but below the TDC group. Furthermore, both the SPD and ASD groups demonstrated equally impaired visuomotor abilities relative to the TDC group. A correlational analysis between cognitive and visuomotor control suggest a relationship between these overlapping control networks., Conclusions: This study supports the importance of direct, phenotypic characterizations of control-based abilities in children with ASD and SPD to personalize characterization and treatment interventions for at-risk children. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)
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- 2018
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7. Chronic stress is associated with reduced circulating hematopoietic progenitor cell number: A maternal caregiving model.
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Aschbacher K, Milush JM, Gilbert A, Almeida C, Sinclair E, Epling L, Grenon SM, Marco EJ, Puterman E, and Epel E
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- Adolescent, Adult, Autism Spectrum Disorder metabolism, Cardiovascular Diseases blood, Caregivers psychology, Cell Count, Child, Child, Preschool, Depression psychology, Female, Humans, Lipid Metabolism, Lipopolysaccharide Receptors immunology, Male, Middle Aged, Risk Factors, Spouses psychology, Young Adult, Autism Spectrum Disorder psychology, Hematopoietic Stem Cells metabolism, Maternal Behavior, Stress, Psychological blood
- Abstract
Background: Chronic psychological stress is a risk factor for cardiovascular disease and mortality. Circulating hematopoietic progenitor cells (CPCs) maintain vascular homeostasis, correlate with preclinical atherosclerosis, and prospectively predict cardiovascular events. We hypothesize that (1) chronic caregiving stress is related to reduced CPC number, and (2) this may be explained in part by negative interactions within the family., Methods: We investigated levels of stress and CPCs in 68 healthy mothers - 31 of these had children with an autism spectrum disorder (M-ASD) and 37 had neurotypical children (M-NT). Participants provided fasting blood samples, and CD45
+ CD34+ KDR+ and CD45+ CD133+ KDR+ CPCs were assayed by flow cytometry. We averaged the blom-transformed scores of both CPCs to create one index. Participants completed the perceived stress scale (PSS), the inventory for depressive symptoms (IDS), and reported on daily interactions with their children and partners, averaged over 7 nights., Results: M-ASD exhibited lower CPCs than M-NT (Cohen's d=0.83; p⩽0.01), controlling for age, BMI, and physical activity. Across the whole sample, positive interactions were related to higher CPCs, and negative interactions to lower CPCs (allp's<0.05). The adverse effects of group on CPCs were significantly mediated through negative interactions with the child (indirect β=-0.24, p⩽0.01). In the full model, greater age (β=-0.19, p=0.04), BMI (β=-0.18, p=0.04), and negative interactions with the child (β=-0.33, p<0.01) were independently associated with lower CPCs. M-ASD had a less healthy lipid profile (total cholesterol/HDL), which in turn, was associated with lower CPCs., Conclusions: Chronic stress adversely impacts CPC number, an early-stage biomarker that predicts subclinical atherosclerosis and future CVD events, independent of traditional cardiovascular risk factors and inflammatory factors. Among maternal caregivers, child-related interpersonal stress appears to be a key psychological predictor of stress-related CVD risk., (Copyright © 2016 Elsevier Inc. All rights reserved.)- Published
- 2017
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8. Shared and Divergent Auditory and Tactile Processing in Children with Autism and Children with Sensory Processing Dysfunction Relative to Typically Developing Peers.
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Demopoulos C, Brandes-Aitken AN, Desai SS, Hill SS, Antovich AD, Harris J, and Marco EJ
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- Acoustic Stimulation, Attention Deficit Disorder with Hyperactivity diagnosis, Attention Deficit Disorder with Hyperactivity etiology, Child, Disability Evaluation, Functional Laterality, Humans, Male, Neuropsychological Tests, Severity of Illness Index, Autism Spectrum Disorder complications, Autistic Disorder complications, Developmental Disabilities complications, Perceptual Disorders etiology, Sensation Disorders etiology, Touch physiology
- Abstract
The aim of this study was to compare sensory processing in typically developing children (TDC), children with Autism Spectrum Disorder (ASD), and those with sensory processing dysfunction (SPD) in the absence of an ASD. Performance-based measures of auditory and tactile processing were compared between male children ages 8-12 years assigned to an ASD (N=20), SPD (N=15), or TDC group (N=19). Both the SPD and ASD groups were impaired relative to the TDC group on a performance-based measure of tactile processing (right-handed graphesthesia). In contrast, only the ASD group showed significant impairment on an auditory processing index assessing dichotic listening, temporal patterning, and auditory discrimination. Furthermore, this impaired auditory processing was associated with parent-rated communication skills for both the ASD group and the combined study sample. No significant group differences were detected on measures of left-handed graphesthesia, tactile sensitivity, or form discrimination; however, more participants in the SPD group demonstrated a higher tactile detection threshold (60%) compared to the TDC (26.7%) and ASD groups (35%). This study provides support for use of performance-based measures in the assessment of children with ASD and SPD and highlights the need to better understand how sensory processing affects the higher order cognitive abilities associated with ASD, such as verbal and non-verbal communication, regardless of diagnostic classification.
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- 2015
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9. Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities
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D'Angelo, D., Lebon, S., Chen, Q., Martin-Brevet, S., Snyder, L. G., Hippolyte, L., Hanson, E., Maillard, A. M., Faucett, W. A., Mace, A., Pain, A., Bernier, R., Chawner, S. J. R. A., David, A., Andrieux, J., Aylward, E., Baujat, G., Caldeira, I., Conus, P., Ferrari, C., Forzano, F., Gerard, M., Goin-Kochel, R. P., Grant, E., Hunter, J. V., Isidor, B., Jacquette, A., Jonch, A. E., Keren, B., Lacombe, D., Le Caignec, C., Martin, C. L., Mannik, K., Metspalu, A., Mignot, C., Mukherjee, P., Owen, M. J., Passeggeri, M., Rooryck-Thambo, C., Rosenfeld, J. A., Spence, S. J., Steinman, K. J., Tjernagel, J., Van Haelst, M., Shen, Y., Draganski, B., Sherr, E. H., Ledbetter, D. H., van den Bree, M. B. M., Beckmann, J. S., Spiro, J. E., Reymond, A., Jacquemont, S., Chung, W. K., Knoers, N. V. A. M., Martinet, D., Belfiore, M., Cuvellier, J. -C., Devries, B., Delrue, M. -A., Doco-Fenzy, M., Lebel, R., Leheup, B., Lewis, S., Mencarelli, M. A., Minet, J. -C., Vincent-Delorme, C., Moerman, A., Mucciolo, M., Ounap, K., Rajcan-Separovic, E., Renieri, A., Sanlaville, D., Faas, B. H., Koolen, D. A., Vulto-Van Silfhout, A., de Leeuw, N., Rosanfeld, J. A., Filges, I., Achatz, E., Roetzer, K. M., Bonneau, D., Guichet, A., Lazaro, L., Plessis, G., Kroisel, P. M., Reis, A., Jonveaux, P., Chantot-Bastaraud, S., Rauch, A., Demeer, B., Nordgren, A., Labalme, A., Ferrarini, A., Ramelli, G. P., Guilmatre, A., Joly-Helas, G., Haize, S., Layet, V., Le Gallic, S., de Freminville, B., Touraine, R., Van Binsbergen, E., Mathieu-Dramard, M., Barth, M., Blaumeiser, B., Masurel, A., Cailler, P., Olivier-Faivre, L., Malacarne, M., Coutton, C., Dieterich, K., Satre, V., Wallgren-Pettersson, C., Tensgrom, C., Kaksonen, S., Duban-Bedu, B., Holder, M., Rossi, M., Gaillard, D., Bock, D., Bednarek, N., Guillin, O., Bizzarri, V., Flori, E., Silengo, M., Kooy, R. F., Aboura, A., Beri, M., Delobel, B., Drunat, S., Jaros, Z., Kolk, A., Reigo, A., Zufferey, F., Beckmann, N., Faravelli, F., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A. L., Benedetti, M., Berg, J., Berman, J., Berry, L. N., Bibb, A. L., Blaskey, L., Brennan, J., Brewton, C. M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A. G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Endre, J., Evans, Y. L., Findlay, A., Fischbach, G. D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S. E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F. I., Jenkins, J., Jeremy, R. J., Johnson, K., Kanne, S. M., Kessler, S., Khan, S. Y., Ku, M., Kuschner, E., Laakman, A. L., Lam, P., Lasala, M. W., Lee, H., La, K., Levy, S., Lian, A., Llorens, A. V., Loftus, K., Luks, T. L., Marco, E. J., Martin, S., Martin, A. J., Marzano, G., Masson, C., Mcgovern, K. E., Keehn, R. M., Miller, D. T., Miller, F. K., Moss, T. J., Murray, R., Nagarajan, S. S., Nowell, K. P., Owen, J., Paal, A. M., Packer, A., Page, P. Z., Paul, B. M., Peters, A., Peterson, D., Poduri, A., Pojman, N. J., Porche, K., Proud, M. B., Qasmieh, S., Ramocki, M. B., Reilly, B., Roberts, T. P. L., Shaw, D., Sinha, T., Smith, B., Snow, A., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., Wolken, A., Blaumeiser, Bettina, Kooy, Frank, Other departments, Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study, 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, Knoers, VA., Martinet, D., Belfiore, M., Cuvellier, JC., de Vries, B., Delrue, MA., Doco-Fenzy, M., Lebel, R., Leheup, B., Lewis, S., Mencarelli, MA., Minet, JC., Vincent-Delorme, C., Moerman, A., Mucciolo, M., Ounap, K., Rajcan-Separovic, E., Renieri, A., Sanlaville, D., Faas, BH., Koolen, DA., Vulto-van Silfhout, A., de Leeuw, N., Rosenfeld, JA., Filges, I., Achatz, E., Roetzer, KM., Bonneau, D., Guichet, A., Lazaro, L., Plessis, G., Kroisel, PM., Reis, A., Jonveaux, P., Chantot-Bastaraud, S., Rauch, A., Demeer, B., Nordgren, A., Labalme, A., Ferrarini, A., Ramelli, GP., Guilmatre, A., Joly-Helas, G., Haize, S., Layet, V., Le Gallic, S., de Fréminville, B., Touraine, R., Van Binsbergen, E., Mathieu-Dramard, M., Barth, M., Blaumeiser, B., Masurel, A., Cailler, P., Olivier-Faivre, L., Malacarne, M., Coutton, C., Dieterich, K., Satre, V., Wallgren-Pettersson, C., Tensgrom, C., Kaksonen, S., Duban-Bedu, B., Holder, M., Rossi, M., Gaillard, D., Bock, D., Bednarek, N., Guillin, O., Bizzarri, V., Flori, E., Silengo, M., Kooy, RF., Aboura, A., Beri, M., Delobel, B., Drunat, S., Jaros, Z., Kolk, A., Reigo, A., Zufferey, F., Beckmann, N., Faravelli, F., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, AL., Benedetti, M., Berg, J., Berman, J., Berry, LN., Bibb, AL., Blaskey, L., Brennan, J., Brewton, CM., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, AG., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, JE., Evans, YL., Findlay, A., Fischbach, GD., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, SE., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, FI., Jenkins J.<Suffix>3rd</Suffix>, Jeremy, RJ., Johnson, K., Kanne, SM., Kessler, S., Khan, SY., Ku, M., Kuschner, E., Laakman, AL., Lam, P., Lasala, MW., Lee, H., LaGuerre, K., Levy, S., Lian Cavanagh, A., Llorens, AV., Loftus Campe, K., Luks, TL., Marco, EJ., Martin, S., Martin, AJ., Marzano, G., Masson, C., McGovern, KE., McNally Keehn, R., Miller, DT., Miller, FK., Moss, TJ., Murray, R., Nagarajan, SS., Nowell, KP., Owen, J., Paal, AM., Packer, A., Page, PZ., Paul, BM., Peters, A., Peterson, D., Poduri, A., Pojman, NJ., Porche, K., Proud, MB., Qasmieh, S., Ramocki, MB., Reilly, B., Roberts, TP., Shaw, D., Sinha, T., Smith-Packard, B., Snow Gallagher, A., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., Wolken, A., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
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Male ,0301 basic medicine ,Proband ,Pediatrics ,Autism Spectrum Disorder ,Developmental Disabilities ,Chromosome Disorders ,Comorbidity ,Nonverbal learning disorder ,Cohort Studies ,Cognition ,0302 clinical medicine ,Cerebellum ,Chromosome Duplication ,Gene duplication ,Copy-number variation ,Non-U.S. Gov't ,Child ,2. Zero hunger ,Intelligence quotient ,Research Support, Non-U.S. Gov't ,Middle Aged ,Psychiatry and Mental health ,Microcephaly ,Female ,Schizophrenic Psychology ,Chromosome Deletion ,Psychology ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Human ,Adult ,medicine.medical_specialty ,Adolescent ,DNA Copy Number Variations ,Research Support ,Nervous System Malformations ,Article ,Chromosomes ,Young Adult ,03 medical and health sciences ,Intellectual Disability ,Journal Article ,medicine ,Humans ,Autistic Disorder ,Preschool ,Psychiatry ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Epilepsy ,Pair 16 ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Case-control study ,Autism Spectrum Disorder/epidemiology ,Autism Spectrum Disorder/genetics ,Autistic Disorder/epidemiology ,Autistic Disorder/genetics ,Case-Control Studies ,Cerebellum/abnormalities ,Child, Preschool ,Chromosome Disorders/epidemiology ,Chromosome Disorders/genetics ,Chromosomes, Human, Pair 16/genetics ,Developmental Disabilities/epidemiology ,Developmental Disabilities/genetics ,Epilepsy/epidemiology ,Epilepsy/genetics ,Intellectual Disability/epidemiology ,Intellectual Disability/genetics ,Microcephaly/epidemiology ,Microcephaly/genetics ,Nervous System Malformations/epidemiology ,Nervous System Malformations/genetics ,Schizophrenia/epidemiology ,Schizophrenia/genetics ,medicine.disease ,030104 developmental biology ,Chromosomes, Human, Pair 16 ,Schizophrenia ,Autism ,Human medicine ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 167711.pdf (Publisher’s version ) (Closed access) IMPORTANCE: The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES: To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS: This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES: Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS: Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE: The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.
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- 2016
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10. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders
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Laurent Pasquier, Anne V. Snow, David T. Miller, Louise Harewood, Christina Triantafallou, Timothy P.L. Roberts, Leighton B. Hinkley, Zili Chu, Louis Vallée, Alyss Lian Cavanagh, Evica Rajcan-Separovic, Patricia Blanchet, Fiona Miller, Robin P. Goin-Kochel, Beau Reilly, Bettina Cerban, Vanessa Siffredi, Bridget A. Fernandez, Roger Vaughan, Brianna M. Paul, Fanny Morice-Picard, Elisabeth Flori, Dominique Campion, Gérard Didelot, Anne Philippe, Christa Lese Martin, Srikantan S. Nagarajan, Joris Andrieux, Jacques Puechberty, Marie Pierre Cordier, Jill V. Hunter, Ellen van Binsbergen, Catherine Vincent-Delorme, Vivek Swarnakar, Jean Marie Cuisset, Monica Proud, Patrick Callier, Bert B.A. de Vries, Jeffrey I. Berman, Sarah J. Spence, Alexandra Bowe, Wendy K. Chung, Katy Ankenman, Katherine Hines, Sarah E. Gobuty, Philippe Jonveaux, Lisa Blaskey, Alice Goldenberg, Sylvie Jaillard, Alessandra Renieri, Anne M. Maillard, Tracy Luks, Lee Anne Green Snyder, Elliott H. Sherr, Sarah Y. Khan, Fabienne Prieur, Simon A. Zwolinski, Andres Metspalu, Ghislaine Plessis, Jean Chiesa, Rita J. Jeremy, Valérie Malan, Michèle Mathieu-Dramard, Loyse Hippolyte, Bethanny Smith-Packard, Andrea M. Paal, Bénédicte Duban Bedu, Claudine Rieubland, Jordan Burko, Sylvie Joriot, Philippe Conus, Dominique Bonneau, Benoit Arveiler, Nicole de Leeuw, Allison G. Dempsey, John E. Spiro, Julia Wenegrat, Bertrand Isidor, Cédric Le Caignec, Kyle J. Steinman, Bruno Delobel, Ashlie Llorens, Jacques S. Beckmann, Kelly Johnson, Sean Ackerman, Polina Bukshpun, Silvia Garza, Alexandre Reymond, Damien Sanlaville, Ellen Hanson, Martine Doco-Fenzy, Jacques Thonney, Mari Wakahiro, Juliane Hoyer, Jacqueline Vigneron, Katrin Õunap, Arthur L. Beaudet, Mandy Barker, Nicole Visyak, Sonia Bouquillon, W. Andrew Faucett, Raphael Bernier, Sudha Kilaru Kessler, Audrey Lynn Bibb, Dennis Shaw, R. Frank Kooy, Suzanne M E Lewis, Anna L. Laakman, Nicholas J. Pojman, Hubert Journel, Laura Bernardini, Arianne Stevens, Julia P. Owen, Rebecca Mc Nally Keehn, Stéphanie Selmoni, Sébastien Lebon, Aurélien Macé, Bruno Leheup, Saba Qasmieh, Zoltán Kutalik, Anita Rauch, Yiping Shen, Elysa J. Marco, Nathalie Van der Aa, Carina Ferrari, Noam D. Beckmann, Delphine Héron, Jennifer Tjernage, Benjamin Aaronson, Albert David, Marie Pierre Lemaitre, Muriel Holder, Eve Õiglane-Shlik, Anneke T. Vulto-van Silfhout, Flore Zufferey, Constance Atwell, Marta Benedetti, Ellen Grant, Jenna Elgin, Patricia Z. Page, Caroline Rooryck, Randy L. Buckner, Qixuan Chen, Laurence Faivre, Sébastien Jacquemont, Kerri P. Nowell, Florence Fellmann, Disciglio Vittoria, Katharina Magdalena Rötzer, Hana Lee, Alastair J. Martin, Marion Greenup, David H. Ledbetter, Katrin Männik, Morgan W. Lasala, Jennifer Gerdts, Hanalore Alupay, Florence Petit, Elizabeth Aylward, Gerald D. Fischbach, Mafalda Mucciolo, Maxwell Cheong, Gabriela Marzano, Frédérique Béna, Danielle Martinet, Timothy J. Moss, Odile Boute, Jennifer Olson, Marco Belfiore, Christina Fagerberg, Corby L. Dale, Robert M. Witwicki, Yolanda L. Evans, Melissa B. Ramocki, Marie-Claude Addor, Christèle Dubourg, Mariken Ruiter, Tuhin K. Sinha, Mieke M. van Haelst, Alan Packer, Kathleen E. McGovern, Christie M. Brewton, Stephen M. Kanne, Richard I. Fisher, Tracey Ward, Sophie Dupuis-Girod, Pratik Mukherjee, Simons VIP Consortium, 16p11.2 European Consortium, Addor, MC., Arveiler, B., Belfiore, M., Bena, F., Bernardini, L., Blanchet, P., Bonneau, D., Boute, O., Callier, P., Campion, D., Chiesa, J., Cordier, MP., Cuisset, JM., David, A., de Leeuw, N., de Vries, B., Didelot, G., Doco-Fenzy, M., Bedu, BD., Dubourg, C., Dupuis-Girod, S., Fagerberg, CR., Faivre, L., Fellmann, F., Fernandez, BA., Fisher, R., Flori, E., Goldenberg, A., Heron, D., Holder, M., Hoyer, J., Isidor, B., Jaillard, S., Jonveaux, P., Joriot, S., Journel, H., Kooy, F., le Caignec, C., Leheup, B., Lemaitre, MP., Lewis, S., Malan, V., Mathieu-Dramard, M., Metspalu, A., Morice-Picard, F., Mucciolo, M., Oiglane-Shlik, E., Ounap, K., Pasquier, L., Petit, F., Philippe, A., Plessis, G., Prieur, F., Puechberty, J., Rajcan-Separovic, E., Rauch, A., Renieri, A., Rieubland, C., Rooryck, C., Rötzer, KM., Ruiter, M., Sanlaville, D., Selmoni, S., Shen, Y., Siffredi, V., Thonney, J., Vallée, L., van Binsbergen, E., Van der Aa, N., van Haelst MM., Vigneron, J., Vincent-Delorme, C., Vittoria, D., Vulto-van Silfhout AT., Witwicki, RM., Zwolinski, SA., Bowe, A., Beaudet, AL., Brewton, CM., Chu, Z., Dempsey, AG., Evans, YL., Garza, S., Kanne, SM., Laakman, AL., Lasala, MW., Llorens, AV., Marzano, G., Moss, TJ., Nowell, KP., Proud, MB., Chen, Q., Vaughan, R., Berman, J., Blaskey, L., Hines, K., Kessler, S., Khan, SY., Qasmieh, S., Bibb, AL., Paal, AM., Page, PZ., Smith-Packard, B., Buckner, R., Burko, J., Cavanagh, AL., Cerban, B., Snow, AV., Snyder, LG., Keehn, RM., Miller, DT., Miller, FK., Olson, JE., Triantafallou, C., Visyak, N., Atwell, C., Benedetti, M., Fischbach, GD., Greenup, M., Packer, A., Bukshpun, P., Cheong, M., Dale, C., Gobuty, SE., Hinkley, L., Jeremy, RJ., Lee, H., Luks, TL., Marco, EJ., Martin, AJ., McGovern, KE., Nagarajan, SS., Owen, J., Paul, BM., Pojman, NJ., Sinha, T., Swarnakar, V., Wakahiro, M., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Elgin, J., Gerdts, J., Johnson, K., Reilly, B., Shaw, D., Stevens, A., Ward, T., Wenegrat, J., Other departments, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Pontchaillou [Rennes], Department of Medical Genetics, Université de Lausanne (UNIL), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Texas Children's Hospital [Houston, USA], Department of pediatrics, Primary palliative Care Research Group, Community Health Sciences, General Practice Section, University of Edinburgh, Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developmental Brain and Behaviour Unit, University of Southampton, Institute of Molecular and Cell Biology, University of Tartu, Department of Human Genetics, UCLA, University of California [Los Angeles] (UCLA), University of California-University of California-Semel Institute, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Lausanne = University of Lausanne (UNIL), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), University of California (UC)-University of California (UC)-Semel Institute, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and Kooy, Frank
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Heterozygote ,Adolescent ,[SDV]Life Sciences [q-bio] ,Developmental Disabilities ,Biology ,Body Mass Index ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Gene Order ,Genetics ,medicine ,Humans ,Copy-number variation ,Clinical genetics ,Obesity ,Young adult ,Child ,Genetics (clinical) ,030304 developmental biology ,Child Development Disorders, Pervasive/diagnosis ,Child Development Disorders, Pervasive/genetics ,Chromosome Deletion ,Chromosomes, Human, Pair 16 ,Developmental Disabilities/diagnosis ,Developmental Disabilities/genetics ,Female ,Intelligence Tests ,Phenotype ,Syndrome ,2. Zero hunger ,Psychiatry ,0303 health sciences ,Intelligence quotient ,Neuropsychology ,Complex traits ,medicine.disease ,Comorbidity ,3. Good health ,Autism spectrum disorder ,Child Development Disorders, Pervasive ,Autism ,Medical genetics ,Human medicine ,Copy-Number Variation ,030217 neurology & neurosurgery - Abstract
Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.
- Published
- 2012
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