1. Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities
- Author
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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)
- Subjects
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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