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, Lee Anne Green Snyder, Rebecca Mc Nally 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 journalArticlepeer-review

163 Scopus citations


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 (US)
Pages (from-to)660-668
Number of pages9
JournalJournal of medical genetics
Issue number10
StatePublished - Oct 2012
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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