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 Harewood,Jill 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 Béna,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 B.A. de Vries,Gérard Didelot,Martine Doco-Fenzy,Bénédicte Duban Bedu,Christèle Dubourg,Sophie Dupuis-Girod,Christina Fagerberg,Laurence Faivre,Florence Fellmann,Bridget A. Fernandez,Richard I. Fisher,Elisabeth Flori,Alice Goldenberg,Delphine Héron,Muriel Holder,Juliane Hoyer,Bertrand Isidor,Sylvie Jaillard,Philippe Jonveaux,Sylvie Joriot,Hubert Journel,R. Frank Kooy,Cédric Le Caignec,Bruno Leheup,Marie Pierre Lemaitre,Suzanne M E Lewis,Valérie Malan,Michèle Mathieu-Dramard,Andres Metspalu,Fanny Morice-Picard,Mafalda Mucciolo,Eve Õiglane-Shlik,Katrin Õunap,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 Llorens,Gabriela Marzano,Timothy J. Moss,Kerri P. Nowell,Monica Proud,Qixuan Chen,Roger Vaughan,Jeffrey I. Berman,Lisa Blaskey,Katherine Hines,Sudha Kilaru Kessler,Sarah Y. Khan,Saba Qasmieh,Audrey Lynn Bibb,Andrea M. Paal,Patricia Z. Page,Bethanny Smith-Packard,Randy L. Buckner,Jordan Burko,Alyss Lian Cavanagh,Bettina Cerban,Anne V. Snow,Lee Anne Green Snyder,Rebecca Mc Nally Keehn,David T. Miller,Fiona Miller,Jennifer Olson,Christina Triantafallou,Nicole Visyak,Constance Atwell,Marta Benedetti,Gerald D. Fischbach,Marion Greenup,Alan Packer,Polina Bukshpun,Maxwell Cheong,Corby L. Dale,Sarah E. Gobuty,Leighton B. Hinkley,Rita J. Jeremy,Hana Lee,Tracy Luks,Elysa J. Marco,Alastair J. Martin,Kathleen E. McGovern,Srikantan S. Nagarajan,Julia P. Owen,Brianna M. Paul,Nicholas J. Pojman,Tuhin K. 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 +186 more
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TLDR
The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry, and these features are clinically significant and reproducible.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.read more
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A Higher Mutational Burden in Females Supports a “Female Protective Model” in Neurodevelopmental Disorders
Sébastien Jacquemont,Bradley P. Coe,Micha Hersch,Michael H. Duyzend,Niklas Krumm,Sven Bergmann,Sven Bergmann,Jacques S. Beckmann,Jill A. Rosenfeld,Evan E. Eichler,Evan E. Eichler +10 more
TL;DR: It is strongly suggested that females have an increased etiological burden unlinked to rare deleterious variants on the X chromosome.
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Autism genetics: opportunities and challenges for clinical translation.
Jacob A. S. Vorstman,Jeremy R. Parr,Daniel Moreno-De-Luca,Richard Anney,John I. Nurnberger,Joachim Hallmayer +5 more
TL;DR: Findings indicate that aetiological heterogeneity, variable penetrance and genetic pleiotropy are pervasive characteristics of autism genetics.
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Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence
Andres Moreno-De-Luca,Scott M. Myers,Scott M. Myers,Thomas D. Challman,Thomas D. Challman,Daniel Moreno-De-Luca,David W. Evans,David W. Evans,David H. Ledbetter,David H. Ledbetter +9 more
TL;DR: Evidence of variability in the clinical manifestations of individual genetic variants and sharing of genetic causes among clinically distinct brain disorders is consistent with the concept of developmental brain dysfunction, a term used to describe the abnormal brain function underlying a group of neurodevelopmental and neuropsychiatric disorders.
Journal ArticleDOI
Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities.
Debra D'Angelo,Sébastien Lebon,Qixuan Chen,Sandra Martin-Brevet,LeeAnne Green Snyder,Loyse Hippolyte,Ellen Hanson,Anne M. Maillard,W. Andrew Faucett,Aurélien Macé,Aurélien Macé,Aurélie Pain,Raphael Bernier,Samuel J.R.A. Chawner,Albert David,Joris Andrieux,Elizabeth Aylward,Geneviève Baujat,Geneviève Baujat,Ines Caldeira,Philippe Conus,Carrina Ferrari,Francesca Forzano,Marion Gérard,Robin P. Goin-Kochel,Ellen Grant,Jill V. Hunter,Bertrand Isidor,Aurélia Jacquette,Aia Elise Jønch,Boris Keren,Didier Lacombe,Cédric Le Caignec,Christa Lese Martin,Katrin Männik,Katrin Männik,Andres Metspalu,Cyril Mignot,Pratik Mukherjee,Michael John Owen,Marzia Passeggeri,Caroline Rooryck-Thambo,Jill A. Rosenfeld,Sarah J. Spence,Kyle J. Steinman,Jennifer Tjernagel,Mieke M. van Haelst,Yiping Shen,Bogdan Draganski,Elliott H. Sherr,David H. Ledbetter,Marianne Bernadette van den Bree,Jacques S. Beckmann,Jacques S. Beckmann,John E. Spiro,Alexandre Reymond,Sébastien Jacquemont,Sébastien Jacquemont,Wendy K. Chung +58 more
TL;DR: 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.
Journal ArticleDOI
The Cognitive and Behavioral Phenotype of the 16p11.2 Deletion in a Clinically Ascertained Population
Ellen Hanson,Raphael Bernier,Ken Porche,Frank I. Jackson,Robin P. Goin-Kochel,LeeAnne Green Snyder,Anne V. Snow,Arianne S. Wallace,Katherine L. Campe,Yuan Zhang,Qixuan Chen,Debra D'Angelo,Andres Moreno-De-Luca,Patrick T. Orr,K. B. Boomer,David W. Evans,Stephen M. Kanne,Leandra N. Berry,Fiona Miller,Jennifer Olson,Elliot Sherr,Christa Lese Martin,David H. Ledbetter,John E. Spiro,Wendy K. Chung +24 more
TL;DR: Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype.
References
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