A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Anne-Claude Tabet 1, 2, 3, 4 Thomas Rolland 2, 3, 4 Marie Ducloy 2, 3, 4 Jonathan Levy 1 Julien Buratti 2, 3, 4 Alexandre Mathieu 2, 3, 4 Damien Haye 1 Laurence Perrin 1 Céline Dupont 1 Sandrine Passemard 1 Yline Capri 1 Alain Verloes 1 Séverine Drunat 1 Boris Keren 5 Cyril Mignot 6 Isabelle Marey 6 Aurélia Jacquette 6 Sandra Whalen 6 Jean Pipiras 7 Jean Benzacken 7 Sandra Chantot-Bastaraud 8 Alexandra Afenjar 9 Delphine Heron 9 Cédric Le Caignec 10 Claire Beneteau 10 Olivier Pichon 10 Bertrand Isidor 10 Albert David 10 Laïla El Khattabi 11 Stephan Kemeny 12 Laetitia Gouas 12 Philippe Vago 12 Anne-Laure Mosca-Boidron 13 Laurence Faivre 14 Chantal Missirian 15 Nicole Philip 15 Damien Sanlaville 16 Patrick Edery 17 Véronique Satre 18 Charles Coutton 18 Françoise Devillard 18 Klaus Dieterich 18 Marie-Laure Vuillaume 19 Caroline Rooryck 19 Didier Lacombe 19 Lucile Pinson 20 Vincent Gatinois 20 Jacques Puechberty 20 Jean Chiesa 21 James Lespinasse Christèle Dubourg 22 Chloé Quélin 22 Mélanie Fradin 22 Hubert Journel Annick Toutain 23 Dominique Martin-Coignard Abdelamdjid Benmansour 1 Claire Leblond 2, 3, 4 Roberto Toro 2, 3, 4 Fréderique Amsellem 24 Richard Delorme 2, 3, 4, 24 Thomas Bourgeron 2, 3, 4
Abstract : Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes theSHANK3gene.SHANK3is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inheritedSHANK3deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.
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Anne-Claude Tabet, Thomas Rolland, Marie Ducloy, Jonathan Levy, Julien Buratti, et al.. A framework to identify contributing genes in patients with Phelan-McDermid syndrome. Genomic Medicine, Springer Verlag, 2017, 2, pp.32. ⟨10.1038/s41525-017-0035-2⟩. ⟨hal-01738521⟩

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