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

Anne-Claude Tabet; Thomas Rolland; Marie Ducloy; Jonathan Levy; Julien Buratti; Mathieu Alexandre; Damien Haye; Laurence Perrin; Céline Dupont; Sandrine Passemard; Yline Capri; Alain Verloes; Séverine Drunat; Boris Keren; Cyril Mignot; Isabelle Marey; Aurélia Jacquette; Sandra Whalen; Jean Pipiras; Jean Benzacken; Sandra Chantot-Bastaraud; Alexandra Afenjar; Delphine Heron; Cédric Le Caignec; Claire Beneteau; Olivier Pichon; Bertrand Isidor; Albert David; Laïla El Khattabi; Stephan Kemeny; Laetitia Gouas; Philippe Vago; Anne-Laure Mosca-Boidron; Laurence Faivre; Chantal Missirian; Nicole Philip; Damien Sanlaville; Patrick Edery; Véronique Satre; Charles Coutton; Françoise Devillard; Klaus Dieterich; Marie-Laure Vuillaume; Caroline Rooryck; Didier Lacombe; Lucile Pinson; Vincent Gatinois; Jacques Puechberty; Jean Chiesa; James Lespinasse; Christèle Dubourg; Chloé Quélin; Mélanie Fradin; Hubert Journel; Annick Toutain; Dominique Martin-Coignard; Abdelamdjid Benmansour; Claire Leblond; Roberto Toro; Fréderique Amsellem; Richard Delorme; Thomas Bourgeron

doi:10.1038/s41525-017-0035-2

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

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

Anne-Claude Tabet, Thomas Rolland, Marie Ducloy, Jonathan Levy, Julien Buratti, Mathieu Alexandre, Damien Haye, Laurence Perrin, Céline Dupont, Sandrine Passemard, …

Genomic Medicine, Vol.2

2017

DOI: https://doi.org/10.1038/s41525-017-0035-2

PMCID: PMC5677962

PMID: 29263841

Résumé

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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Titre: A framework to identify contributing genes in patients with Phelan-McDermid syndrome
Créateurs - sans rôle: Anne-Claude Tabet - Assistance Publique – Hôpitaux de Paris
Thomas Rolland - Institut Pasteur
Marie Ducloy - Institut Pasteur
Jonathan Levy - Hôpital Robert-Debré
Julien Buratti - Institut Pasteur
Mathieu Alexandre - Sorbonne Paris Cité
Damien Haye - Assistance Publique – Hôpitaux de Paris
Laurence Perrin - Hôpital Robert-Debré
Céline Dupont - Assistance Publique – Hôpitaux de Paris
Sandrine Passemard - Assistance Publique – Hôpitaux de Paris
Yline Capri - Hôpital Robert-Debré
Alain Verloes - Assistance Publique – Hôpitaux de Paris
Séverine Drunat - Assistance Publique – Hôpitaux de Paris
Boris Keren - Sorbonne Université
Cyril Mignot - Sorbonne Université
Isabelle Marey - Assistance Publique – Hôpitaux de Paris
Aurélia Jacquette - Pitié-Salpêtrière Hospital
Sandra Whalen - Assistance Publique – Hôpitaux de Paris
Jean Pipiras - Hôpital Jean-Verdier
Jean Benzacken - Hôpital Jean-Verdier
Sandra Chantot-Bastaraud - Assistance Publique – Hôpitaux de Paris
Alexandra Afenjar - Assistance Publique – Hôpitaux de Paris
Delphine Heron - Assistance Publique – Hôpitaux de Paris
Cédric Le Caignec - Service de génétique médicale - Unité de génétique clinique [Nantes]
Claire Beneteau - Service de génétique médicale - Unité de génétique clinique [Nantes]
Olivier Pichon - Service de génétique médicale - Unité de génétique clinique [Nantes]
Bertrand Isidor - Service de génétique médicale - Unité de génétique clinique [Nantes]
Albert David - Service de génétique médicale - Unité de génétique clinique [Nantes]
Laïla El Khattabi - Assistance Publique – Hôpitaux de Paris
Stephan Kemeny - Centre Hospitalier Universitaire de Clermont-Ferrand
Laetitia Gouas - Centre Hospitalier Universitaire de Clermont-Ferrand
Philippe Vago - Centre Hospitalier Universitaire de Clermont-Ferrand
Anne-Laure Mosca-Boidron - Laboratoire de cytogénétique (CHU de Dijon)
Laurence Faivre - Maison des Sciences sociales et des Humanités de Dijon
Chantal Missirian - Hôpital de la Timone
Nicole Philip - Hôpital de la Timone
Damien Sanlaville - Hospices Civils de Lyon
Patrick Edery - Service de génétique [Hôpital Louis Pradel - HCL]
Véronique Satre - Centre Hospitalier Universitaire [CHU Grenoble]
Charles Coutton - Centre Hospitalier Universitaire [CHU Grenoble]
Françoise Devillard - Centre Hospitalier Universitaire [CHU Grenoble]
Klaus Dieterich - Centre Hospitalier Universitaire [CHU Grenoble]
Marie-Laure Vuillaume - Service de génétique médicale
Caroline Rooryck - Bordeaux Population Health
Didier Lacombe - Bordeaux Population Health
Lucile Pinson - Centre Hospitalier Universitaire de Montpellier
Vincent Gatinois - Centre Hospitalier Universitaire de Montpellier
Jacques Puechberty - Centre Hospitalier Universitaire de Montpellier
Jean Chiesa - Université de Nîmes
James Lespinasse - Centre Hospitalier Métropole Savoie
Christèle Dubourg - Centre Hospitalier Universitaire de Rennes
Chloé Quélin - Centre Hospitalier Universitaire de Rennes
Mélanie Fradin - Centre Hospitalier Universitaire de Rennes
Hubert Journel - Centre hospitalier Bretagne Atlantique
Annick Toutain - Centre Hospitalier Universitaire de Tours
Dominique Martin-Coignard - Centre Hospitalier Le Mans (CH Le Mans)
Abdelamdjid Benmansour - Hôpital Robert-Debré
Claire Leblond - Sorbonne Paris Cité
Roberto Toro - Délégation Paris 7
Fréderique Amsellem - Hôpital Robert-Debré
Richard Delorme - Assistance Publique – Hôpitaux de Paris
Thomas Bourgeron - Délégation Paris 7
Détails de publication: Genomic Medicine, Vol.2
Note de subvention: This work was funded by the Institut Pasteur, the Bettencourt-Schueller Foundation, Centre National de la Recherche Scientifique, University Paris Diderot, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Orange Foundation, the FondaMental Foundation, the GenMed Labex and the BioPsy Labex. The research leading to these results has received funding from the ERA-Net NEURON Cofund Programme under “Horizon 2020” (SynPathy project), the ANR SynDivAutism, the Human Brain Project, and from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution.
Identifiants: 99121969109311
Unité académique: Institut des Biomolécules Max Mousseron - IBMM
Langue: English
Type de ressource: Journal article
Champs locaux: hal-01738521