A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

Flore Zufferey, Elliott H. Sherr, Noam D. Beckmann, Ellen Hanson, Anne M. Maillard, Loyse Hippolyte, Aurélien Macé, Carina Ferrari, Zoltán Kutalik, Joris Andrieux, Elizabeth Aylward, Mandy Barker, Raphael Bernier, Sonia Bouquillon, Philippe Conus, Bruno Delobel, W. Andrew Faucett, Robin P. Goin-Kochel, Ellen Grant, Louise HarewoodJill V. Hunter, Sébastien Lebon, David H. Ledbetter, Christa Lese Martin, Katrin Männik, Danielle Martinet, Pratik Mukherjee, Melissa B. Ramocki, Sarah J. Spence, Kyle J. Steinman, Jennifer Tjernage, John E. Spiro, Alexandre Reymond, Jacques S. Beckmann, Wendy K. Chung, Sébastien Jacquemont, Marie Claude Addor, Benoit Arveiler, Marco Belfiore, Frédérique Bena, Laura Bernardini, Patricia Blanchet, Dominique Bonneau, Odile Boute, Patrick Callier, Dominique Campion, Jean Chiesa, Marie Pierre Cordier, Jean Marie Cuisset, Albert David, Nicole De Leeuw, Bert De Vries, Gérard Didelot, Martine Doco-Fenzy, Bénédicte Duban Bedu, Christèle Dubourg, Sophie Dupuis-Girod, Christina R. Fagerberg, Laurence Faivre, Florence Fellmann, Bridget A. Fernandez, Richard Fisher, Elisabeth Flori, Alice Goldenberg, Delphine Heron, Muriel Holder, Juliane Hoyer, Bertrand Isidor, Sylvie Jaillard, Philippe Jonveaux, Sylvie Joriot, Hubert Journel, Frank Kooy, Cédric le Caignec, Bruno Leheup, Marie Pierre Lemaitre, Suzanne Lewis, Valérie Malan, Michèle Mathieu-Dramard, Andres Metspalu, Fanny Morice-Picard, Mafalda Mucciolo, Eve Oiglane-Shlik, Katrin Ounap, Laurent Pasquier, Florence Petit, Anne Philippe, Ghislaine Plessis, Fabienne Prieur, Jacques Puechberty, Evica Rajcan-Separovic, Anita Rauch, Alessandra Renieri, Claudine Rieubland, Caroline Rooryck, Katharina Magdalena Rötzer, Mariken Ruiter, Damien Sanlaville, Stéphanie Selmoni, Yiping Shen, Vanessa Siffredi, Jacques Thonney, Louis Vallée, Ellen Van Binsbergen, Nathalie Van der Aa, Mieke M. Van Haelst, Jacqueline Vigneron, Catherine Vincent-Delorme, Disciglio Vittoria, Anneke T. Vulto-Van Silfhout, Robert M. Witwicki, Simon A. Zwolinski, Alexandra Bowe, Arthur L. Beaudet, Christie M. Brewton, Zili Chu, Allison G. Dempsey, Yolanda L. Evans, Silvia Garza, Stephen M. Kanne, Anna L. Laakman, Morgan W. Lasala, Ashlie V. Llorens, Gabriela Marzano, Timothy J. Moss, Kerri P. Nowell, Monica B. Proud, Qixuan Chen, Roger Vaughan, Jeffrey Berman, Lisa Blaskey, Katherine Hines, Sudha Kessler, Sarah Y. Khan, Saba Qasmieh, Audrey Lynn Bibb, Andrea M. Paal, Patricia Z. Page, Bethanny Smith-Packard, Randy Buckner, Jordan Burko, Alyss Lian Cavanagh, Bettina Cerban, Anne V. Snow, LeeAnne Green Snyder, Rebecca McNally Keehn, David T. Miller, Fiona K. Miller, Jennifer Endre Olson, Christina Triantafallou, Nicole Visyak, Constance Atwell, Marta Benedetti, Gerald D. Fischbach, Marion Greenup, Alan Packer, Polina Bukshpun, Maxwell Cheong, Corby Dale, Sarah E. Gobuty, Leighton Hinkley, Rita J. Jeremy, Hana Lee, Tracy L. Luks, Elysa J. Marco, Alastair J. Martin, Kathleen E. McGovern, Srikantan S. Nagarajan, Julia Owen, Brianna M. Paul, Nicholas J. Pojman, Tuhin Sinha, Vivek Swarnakar, Mari Wakahiro, Hanalore Alupay, Benjamin Aaronson, Sean Ackerman, Katy Ankenman, Jenna Elgin, Jennifer Gerdts, Kelly Johnson, Beau Reilly, Dennis Shaw, Arianne Stevens, Tracey Ward, Julia Wenegrat, Timothy P L Roberts

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)660-668
Number of pages9
JournalJournal of Medical Genetics
Volume49
Issue number10
DOIs
Publication statusPublished - Oct 2012

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Intelligence
Head
Speech Therapy
Psychiatry
Comorbidity
Seizures
Body Mass Index
Obesity
Pediatrics
Phenotype
Brain
Growth
Autism Spectrum Disorder
16p11.2 Deletion Syndrome
Neurodevelopmental Disorders

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Zufferey, F., Sherr, E. H., Beckmann, N. D., Hanson, E., Maillard, A. M., Hippolyte, L., ... Roberts, T. P. L. (2012). A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. Journal of Medical Genetics, 49(10), 660-668. https://doi.org/10.1136/jmedgenet-2012-101203

A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. / Zufferey, Flore; Sherr, Elliott H.; Beckmann, Noam D.; Hanson, Ellen; Maillard, Anne M.; Hippolyte, Loyse; Macé, Aurélien; Ferrari, Carina; Kutalik, Zoltán; Andrieux, Joris; Aylward, Elizabeth; Barker, Mandy; Bernier, Raphael; Bouquillon, Sonia; Conus, Philippe; Delobel, Bruno; Faucett, W. Andrew; Goin-Kochel, Robin P.; Grant, Ellen; Harewood, Louise; Hunter, Jill V.; Lebon, Sébastien; Ledbetter, David H.; Martin, Christa Lese; Männik, Katrin; Martinet, Danielle; Mukherjee, Pratik; Ramocki, Melissa B.; Spence, Sarah J.; Steinman, Kyle J.; Tjernage, Jennifer; Spiro, John E.; Reymond, Alexandre; Beckmann, Jacques S.; Chung, Wendy K.; Jacquemont, Sébastien; Addor, Marie Claude; Arveiler, Benoit; Belfiore, Marco; Bena, Frédérique; Bernardini, Laura; Blanchet, Patricia; Bonneau, Dominique; Boute, Odile; Callier, Patrick; Campion, Dominique; Chiesa, Jean; Cordier, Marie Pierre; Cuisset, Jean Marie; David, Albert; De Leeuw, Nicole; De Vries, Bert; Didelot, Gérard; Doco-Fenzy, Martine; Bedu, Bénédicte Duban; Dubourg, Christèle; Dupuis-Girod, Sophie; Fagerberg, Christina R.; Faivre, Laurence; Fellmann, Florence; Fernandez, Bridget A.; Fisher, Richard; Flori, Elisabeth; Goldenberg, Alice; Heron, Delphine; Holder, Muriel; Hoyer, Juliane; Isidor, Bertrand; Jaillard, Sylvie; Jonveaux, Philippe; Joriot, Sylvie; Journel, Hubert; Kooy, Frank; le Caignec, Cédric; Leheup, Bruno; Lemaitre, Marie Pierre; Lewis, Suzanne; Malan, Valérie; Mathieu-Dramard, Michèle; Metspalu, Andres; Morice-Picard, Fanny; Mucciolo, Mafalda; Oiglane-Shlik, Eve; Ounap, Katrin; Pasquier, Laurent; Petit, Florence; Philippe, Anne; Plessis, Ghislaine; Prieur, Fabienne; Puechberty, Jacques; Rajcan-Separovic, Evica; Rauch, Anita; Renieri, Alessandra; Rieubland, Claudine; Rooryck, Caroline; Rötzer, Katharina Magdalena; Ruiter, Mariken; Sanlaville, Damien; Selmoni, Stéphanie; Shen, Yiping; Siffredi, Vanessa; Thonney, Jacques; Vallée, Louis; Van Binsbergen, Ellen; Van der Aa, Nathalie; Van Haelst, Mieke M.; Vigneron, Jacqueline; Vincent-Delorme, Catherine; Vittoria, Disciglio; Vulto-Van Silfhout, Anneke T.; Witwicki, Robert M.; Zwolinski, Simon A.; Bowe, Alexandra; Beaudet, Arthur L.; Brewton, Christie M.; Chu, Zili; Dempsey, Allison G.; Evans, Yolanda L.; Garza, Silvia; Kanne, Stephen M.; Laakman, Anna L.; Lasala, Morgan W.; Llorens, Ashlie V.; Marzano, Gabriela; Moss, Timothy J.; Nowell, Kerri P.; Proud, Monica B.; Chen, Qixuan; Vaughan, Roger; Berman, Jeffrey; Blaskey, Lisa; Hines, Katherine; Kessler, Sudha; Khan, Sarah Y.; Qasmieh, Saba; Bibb, Audrey Lynn; Paal, Andrea M.; Page, Patricia Z.; Smith-Packard, Bethanny; Buckner, Randy; Burko, Jordan; Cavanagh, Alyss Lian; Cerban, Bettina; Snow, Anne V.; Snyder, LeeAnne Green; Keehn, Rebecca McNally; Miller, David T.; Miller, Fiona K.; Olson, Jennifer Endre; Triantafallou, Christina; Visyak, Nicole; Atwell, Constance; Benedetti, Marta; Fischbach, Gerald D.; Greenup, Marion; Packer, Alan; Bukshpun, Polina; Cheong, Maxwell; Dale, Corby; Gobuty, Sarah E.; Hinkley, Leighton; Jeremy, Rita J.; Lee, Hana; Luks, Tracy L.; Marco, Elysa J.; Martin, Alastair J.; McGovern, Kathleen E.; Nagarajan, Srikantan S.; Owen, Julia; Paul, Brianna M.; Pojman, Nicholas J.; Sinha, Tuhin; Swarnakar, Vivek; Wakahiro, Mari; Alupay, Hanalore; Aaronson, Benjamin; Ackerman, Sean; Ankenman, Katy; Elgin, Jenna; Gerdts, Jennifer; Johnson, Kelly; Reilly, Beau; Shaw, Dennis; Stevens, Arianne; Ward, Tracey; Wenegrat, Julia; Roberts, Timothy P L.

In: Journal of Medical Genetics, Vol. 49, No. 10, 10.2012, p. 660-668.

Research output: Contribution to journalArticle

Zufferey, F, Sherr, EH, Beckmann, ND, Hanson, E, Maillard, AM, Hippolyte, L, Macé, A, Ferrari, C, Kutalik, Z, Andrieux, J, Aylward, E, Barker, M, Bernier, R, Bouquillon, S, Conus, P, Delobel, B, Faucett, WA, Goin-Kochel, RP, Grant, E, Harewood, L, Hunter, JV, Lebon, S, Ledbetter, DH, Martin, CL, Männik, K, Martinet, D, Mukherjee, P, Ramocki, MB, Spence, SJ, Steinman, KJ, Tjernage, J, Spiro, JE, Reymond, A, Beckmann, JS, Chung, WK, Jacquemont, S, 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 & Roberts, TPL 2012, 'A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders', Journal of Medical Genetics, vol. 49, no. 10, pp. 660-668. https://doi.org/10.1136/jmedgenet-2012-101203
Zufferey, Flore ; Sherr, Elliott H. ; Beckmann, Noam D. ; Hanson, Ellen ; Maillard, Anne M. ; Hippolyte, Loyse ; Macé, Aurélien ; Ferrari, Carina ; Kutalik, Zoltán ; Andrieux, Joris ; Aylward, Elizabeth ; Barker, Mandy ; Bernier, Raphael ; Bouquillon, Sonia ; Conus, Philippe ; Delobel, Bruno ; Faucett, W. Andrew ; Goin-Kochel, Robin P. ; Grant, Ellen ; Harewood, Louise ; Hunter, Jill V. ; Lebon, Sébastien ; Ledbetter, David H. ; Martin, Christa Lese ; Männik, Katrin ; Martinet, Danielle ; Mukherjee, Pratik ; Ramocki, Melissa B. ; Spence, Sarah J. ; Steinman, Kyle J. ; Tjernage, Jennifer ; Spiro, John E. ; Reymond, Alexandre ; Beckmann, Jacques S. ; Chung, Wendy K. ; Jacquemont, Sébastien ; Addor, Marie Claude ; Arveiler, Benoit ; Belfiore, Marco ; Bena, Frédérique ; Bernardini, Laura ; Blanchet, Patricia ; Bonneau, Dominique ; Boute, Odile ; Callier, Patrick ; Campion, Dominique ; Chiesa, Jean ; Cordier, Marie Pierre ; Cuisset, Jean Marie ; David, Albert ; De Leeuw, Nicole ; De Vries, Bert ; Didelot, Gérard ; Doco-Fenzy, Martine ; Bedu, Bénédicte Duban ; Dubourg, Christèle ; Dupuis-Girod, Sophie ; Fagerberg, Christina R. ; Faivre, Laurence ; Fellmann, Florence ; Fernandez, Bridget A. ; Fisher, Richard ; Flori, Elisabeth ; Goldenberg, Alice ; Heron, Delphine ; Holder, Muriel ; Hoyer, Juliane ; Isidor, Bertrand ; Jaillard, Sylvie ; Jonveaux, Philippe ; Joriot, Sylvie ; Journel, Hubert ; Kooy, Frank ; le Caignec, Cédric ; Leheup, Bruno ; Lemaitre, Marie Pierre ; Lewis, Suzanne ; Malan, Valérie ; Mathieu-Dramard, Michèle ; Metspalu, Andres ; Morice-Picard, Fanny ; Mucciolo, Mafalda ; Oiglane-Shlik, Eve ; Ounap, Katrin ; Pasquier, Laurent ; Petit, Florence ; Philippe, Anne ; Plessis, Ghislaine ; Prieur, Fabienne ; Puechberty, Jacques ; Rajcan-Separovic, Evica ; Rauch, Anita ; Renieri, Alessandra ; Rieubland, Claudine ; Rooryck, Caroline ; Rötzer, Katharina Magdalena ; Ruiter, Mariken ; Sanlaville, Damien ; Selmoni, Stéphanie ; Shen, Yiping ; Siffredi, Vanessa ; Thonney, Jacques ; Vallée, Louis ; Van Binsbergen, Ellen ; Van der Aa, Nathalie ; Van Haelst, Mieke M. ; Vigneron, Jacqueline ; Vincent-Delorme, Catherine ; Vittoria, Disciglio ; Vulto-Van Silfhout, Anneke T. ; Witwicki, Robert M. ; Zwolinski, Simon A. ; Bowe, Alexandra ; Beaudet, Arthur L. ; Brewton, Christie M. ; Chu, Zili ; Dempsey, Allison G. ; Evans, Yolanda L. ; Garza, Silvia ; Kanne, Stephen M. ; Laakman, Anna L. ; Lasala, Morgan W. ; Llorens, Ashlie V. ; Marzano, Gabriela ; Moss, Timothy J. ; Nowell, Kerri P. ; Proud, Monica B. ; Chen, Qixuan ; Vaughan, Roger ; Berman, Jeffrey ; Blaskey, Lisa ; Hines, Katherine ; Kessler, Sudha ; Khan, Sarah Y. ; Qasmieh, Saba ; Bibb, Audrey Lynn ; Paal, Andrea M. ; Page, Patricia Z. ; Smith-Packard, Bethanny ; Buckner, Randy ; Burko, Jordan ; Cavanagh, Alyss Lian ; Cerban, Bettina ; Snow, Anne V. ; Snyder, LeeAnne Green ; Keehn, Rebecca McNally ; Miller, David T. ; Miller, Fiona K. ; Olson, Jennifer Endre ; Triantafallou, Christina ; Visyak, Nicole ; Atwell, Constance ; Benedetti, Marta ; Fischbach, Gerald D. ; Greenup, Marion ; Packer, Alan ; Bukshpun, Polina ; Cheong, Maxwell ; Dale, Corby ; Gobuty, Sarah E. ; Hinkley, Leighton ; Jeremy, Rita J. ; Lee, Hana ; Luks, Tracy L. ; Marco, Elysa J. ; Martin, Alastair J. ; McGovern, Kathleen E. ; Nagarajan, Srikantan S. ; Owen, Julia ; Paul, Brianna M. ; Pojman, Nicholas J. ; Sinha, Tuhin ; Swarnakar, Vivek ; Wakahiro, Mari ; Alupay, Hanalore ; Aaronson, Benjamin ; Ackerman, Sean ; Ankenman, Katy ; Elgin, Jenna ; Gerdts, Jennifer ; Johnson, Kelly ; Reilly, Beau ; Shaw, Dennis ; Stevens, Arianne ; Ward, Tracey ; Wenegrat, Julia ; Roberts, Timothy P L. / A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. In: Journal of Medical Genetics. 2012 ; Vol. 49, No. 10. pp. 660-668.
@article{623d9f458d6a4e9aadc8234522d83f01,
title = "A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders",
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.",
author = "Flore Zufferey and Sherr, {Elliott H.} and Beckmann, {Noam D.} and Ellen Hanson and Maillard, {Anne M.} and Loyse Hippolyte and Aur{\'e}lien Mac{\'e} and Carina Ferrari and Zolt{\'a}n Kutalik and Joris Andrieux and Elizabeth Aylward and Mandy Barker and Raphael Bernier and Sonia Bouquillon and Philippe Conus and Bruno Delobel and Faucett, {W. Andrew} and Goin-Kochel, {Robin P.} and Ellen Grant and Louise Harewood and Hunter, {Jill V.} and S{\'e}bastien Lebon and Ledbetter, {David H.} and Martin, {Christa Lese} and Katrin M{\"a}nnik and Danielle Martinet and Pratik Mukherjee and Ramocki, {Melissa B.} and Spence, {Sarah J.} and Steinman, {Kyle J.} and Jennifer Tjernage and Spiro, {John E.} and Alexandre Reymond and Beckmann, {Jacques S.} and Chung, {Wendy K.} and S{\'e}bastien Jacquemont and Addor, {Marie Claude} and Benoit Arveiler and Marco Belfiore and Fr{\'e}d{\'e}rique Bena and Laura Bernardini and Patricia Blanchet and Dominique Bonneau and Odile Boute and Patrick Callier and Dominique Campion and Jean Chiesa and Cordier, {Marie Pierre} and Cuisset, {Jean Marie} and Albert David and {De Leeuw}, Nicole and {De Vries}, Bert and G{\'e}rard Didelot and Martine Doco-Fenzy and Bedu, {B{\'e}n{\'e}dicte Duban} and Christ{\`e}le Dubourg and Sophie Dupuis-Girod and Fagerberg, {Christina R.} and Laurence Faivre and Florence Fellmann and Fernandez, {Bridget A.} and Richard Fisher and Elisabeth Flori and Alice Goldenberg and Delphine Heron and Muriel Holder and Juliane Hoyer and Bertrand Isidor and Sylvie Jaillard and Philippe Jonveaux and Sylvie Joriot and Hubert Journel and Frank Kooy and {le Caignec}, C{\'e}dric and Bruno Leheup and Lemaitre, {Marie Pierre} and Suzanne Lewis and Val{\'e}rie Malan and Mich{\`e}le Mathieu-Dramard and Andres Metspalu and Fanny Morice-Picard and Mafalda Mucciolo and Eve Oiglane-Shlik and Katrin Ounap and Laurent Pasquier and Florence Petit and Anne Philippe and Ghislaine Plessis and Fabienne Prieur and Jacques Puechberty and Evica Rajcan-Separovic and Anita Rauch and Alessandra Renieri and Claudine Rieubland and Caroline Rooryck and R{\"o}tzer, {Katharina Magdalena} and Mariken Ruiter and Damien Sanlaville and St{\'e}phanie Selmoni and Yiping Shen and Vanessa Siffredi and Jacques Thonney and Louis Vall{\'e}e and {Van Binsbergen}, Ellen and {Van der Aa}, Nathalie and {Van Haelst}, {Mieke M.} and Jacqueline Vigneron and Catherine Vincent-Delorme and Disciglio Vittoria and {Vulto-Van Silfhout}, {Anneke T.} and Witwicki, {Robert M.} and Zwolinski, {Simon A.} and Alexandra Bowe and Beaudet, {Arthur L.} and Brewton, {Christie M.} and Zili Chu and Dempsey, {Allison G.} and Evans, {Yolanda L.} and Silvia Garza and Kanne, {Stephen M.} and Laakman, {Anna L.} and Lasala, {Morgan W.} and Llorens, {Ashlie V.} and Gabriela Marzano and Moss, {Timothy J.} and Nowell, {Kerri P.} and Proud, {Monica B.} and Qixuan Chen and Roger Vaughan and Jeffrey Berman and Lisa Blaskey and Katherine Hines and Sudha Kessler and Khan, {Sarah Y.} and Saba Qasmieh and Bibb, {Audrey Lynn} and Paal, {Andrea M.} and Page, {Patricia Z.} and Bethanny Smith-Packard and Randy Buckner and Jordan Burko and Cavanagh, {Alyss Lian} and Bettina Cerban and Snow, {Anne V.} and Snyder, {LeeAnne Green} and Keehn, {Rebecca McNally} and Miller, {David T.} and Miller, {Fiona K.} and Olson, {Jennifer Endre} and Christina Triantafallou and Nicole Visyak and Constance Atwell and Marta Benedetti and Fischbach, {Gerald D.} and Marion Greenup and Alan Packer and Polina Bukshpun and Maxwell Cheong and Corby Dale and Gobuty, {Sarah E.} and Leighton Hinkley and Jeremy, {Rita J.} and Hana Lee and Luks, {Tracy L.} and Marco, {Elysa J.} and Martin, {Alastair J.} and McGovern, {Kathleen E.} and Nagarajan, {Srikantan S.} and Julia Owen and Paul, {Brianna M.} and Pojman, {Nicholas J.} and Tuhin Sinha and Vivek Swarnakar and Mari Wakahiro and Hanalore Alupay and Benjamin Aaronson and Sean Ackerman and Katy Ankenman and Jenna Elgin and Jennifer Gerdts and Kelly Johnson and Beau Reilly and Dennis Shaw and Arianne Stevens and Tracey Ward and Julia Wenegrat and Roberts, {Timothy P L}",
year = "2012",
month = "10",
doi = "10.1136/jmedgenet-2012-101203",
language = "English",
volume = "49",
pages = "660--668",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "10",

}

TY - JOUR

T1 - A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders

AU - Zufferey, Flore

AU - Sherr, Elliott H.

AU - Beckmann, Noam D.

AU - Hanson, Ellen

AU - Maillard, Anne M.

AU - Hippolyte, Loyse

AU - Macé, Aurélien

AU - Ferrari, Carina

AU - Kutalik, Zoltán

AU - Andrieux, Joris

AU - Aylward, Elizabeth

AU - Barker, Mandy

AU - Bernier, Raphael

AU - Bouquillon, Sonia

AU - Conus, Philippe

AU - Delobel, Bruno

AU - Faucett, W. Andrew

AU - Goin-Kochel, Robin P.

AU - Grant, Ellen

AU - Harewood, Louise

AU - Hunter, Jill V.

AU - Lebon, Sébastien

AU - Ledbetter, David H.

AU - Martin, Christa Lese

AU - Männik, Katrin

AU - Martinet, Danielle

AU - Mukherjee, Pratik

AU - Ramocki, Melissa B.

AU - Spence, Sarah J.

AU - Steinman, Kyle J.

AU - Tjernage, Jennifer

AU - Spiro, John E.

AU - Reymond, Alexandre

AU - Beckmann, Jacques S.

AU - Chung, Wendy K.

AU - Jacquemont, Sébastien

AU - Addor, Marie Claude

AU - Arveiler, Benoit

AU - Belfiore, Marco

AU - Bena, Frédérique

AU - Bernardini, Laura

AU - Blanchet, Patricia

AU - Bonneau, Dominique

AU - Boute, Odile

AU - Callier, Patrick

AU - Campion, Dominique

AU - Chiesa, Jean

AU - Cordier, Marie Pierre

AU - Cuisset, Jean Marie

AU - David, Albert

AU - De Leeuw, Nicole

AU - De Vries, Bert

AU - Didelot, Gérard

AU - Doco-Fenzy, Martine

AU - Bedu, Bénédicte Duban

AU - Dubourg, Christèle

AU - Dupuis-Girod, Sophie

AU - Fagerberg, Christina R.

AU - Faivre, Laurence

AU - Fellmann, Florence

AU - Fernandez, Bridget A.

AU - Fisher, Richard

AU - Flori, Elisabeth

AU - Goldenberg, Alice

AU - Heron, Delphine

AU - Holder, Muriel

AU - Hoyer, Juliane

AU - Isidor, Bertrand

AU - Jaillard, Sylvie

AU - Jonveaux, Philippe

AU - Joriot, Sylvie

AU - Journel, Hubert

AU - Kooy, Frank

AU - le Caignec, Cédric

AU - Leheup, Bruno

AU - Lemaitre, Marie Pierre

AU - Lewis, Suzanne

AU - Malan, Valérie

AU - Mathieu-Dramard, Michèle

AU - Metspalu, Andres

AU - Morice-Picard, Fanny

AU - Mucciolo, Mafalda

AU - Oiglane-Shlik, Eve

AU - Ounap, Katrin

AU - Pasquier, Laurent

AU - Petit, Florence

AU - Philippe, Anne

AU - Plessis, Ghislaine

AU - Prieur, Fabienne

AU - Puechberty, Jacques

AU - Rajcan-Separovic, Evica

AU - Rauch, Anita

AU - Renieri, Alessandra

AU - Rieubland, Claudine

AU - Rooryck, Caroline

AU - Rötzer, Katharina Magdalena

AU - Ruiter, Mariken

AU - Sanlaville, Damien

AU - Selmoni, Stéphanie

AU - Shen, Yiping

AU - Siffredi, Vanessa

AU - Thonney, Jacques

AU - Vallée, Louis

AU - Van Binsbergen, Ellen

AU - Van der Aa, Nathalie

AU - Van Haelst, Mieke M.

AU - Vigneron, Jacqueline

AU - Vincent-Delorme, Catherine

AU - Vittoria, Disciglio

AU - Vulto-Van Silfhout, Anneke T.

AU - Witwicki, Robert M.

AU - Zwolinski, Simon A.

AU - Bowe, Alexandra

AU - Beaudet, Arthur L.

AU - Brewton, Christie M.

AU - Chu, Zili

AU - Dempsey, Allison G.

AU - Evans, Yolanda L.

AU - Garza, Silvia

AU - Kanne, Stephen M.

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AU - Lasala, Morgan W.

AU - Llorens, Ashlie V.

AU - Marzano, Gabriela

AU - Moss, Timothy J.

AU - Nowell, Kerri P.

AU - Proud, Monica B.

AU - Chen, Qixuan

AU - Vaughan, Roger

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AU - Blaskey, Lisa

AU - Hines, Katherine

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AU - Qasmieh, Saba

AU - Bibb, Audrey Lynn

AU - Paal, Andrea M.

AU - Page, Patricia Z.

AU - Smith-Packard, Bethanny

AU - Buckner, Randy

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AU - Keehn, Rebecca McNally

AU - Miller, David T.

AU - Miller, Fiona K.

AU - Olson, Jennifer Endre

AU - Triantafallou, Christina

AU - Visyak, Nicole

AU - Atwell, Constance

AU - Benedetti, Marta

AU - Fischbach, Gerald D.

AU - Greenup, Marion

AU - Packer, Alan

AU - Bukshpun, Polina

AU - Cheong, Maxwell

AU - Dale, Corby

AU - Gobuty, Sarah E.

AU - Hinkley, Leighton

AU - Jeremy, Rita J.

AU - Lee, Hana

AU - Luks, Tracy L.

AU - Marco, Elysa J.

AU - Martin, Alastair J.

AU - McGovern, Kathleen E.

AU - Nagarajan, Srikantan S.

AU - Owen, Julia

AU - Paul, Brianna M.

AU - Pojman, Nicholas J.

AU - Sinha, Tuhin

AU - Swarnakar, Vivek

AU - Wakahiro, Mari

AU - Alupay, Hanalore

AU - Aaronson, Benjamin

AU - Ackerman, Sean

AU - Ankenman, Katy

AU - Elgin, Jenna

AU - Gerdts, Jennifer

AU - Johnson, Kelly

AU - Reilly, Beau

AU - Shaw, Dennis

AU - Stevens, Arianne

AU - Ward, Tracey

AU - Wenegrat, Julia

AU - Roberts, Timothy P L

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84870280744&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870280744&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2012-101203

DO - 10.1136/jmedgenet-2012-101203

M3 - Article

C2 - 23054248

AN - SCOPUS:84870280744

VL - 49

SP - 660

EP - 668

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 10

ER -