Our team identified the first mutations in the SHANK3 gene, showing it’s role in autism and Phelan-McDermid Syndrome (PMS). Thanks to a donation from the French Association of Phelan-McDermid Syndrome, we will continue the whole genome sequencing of PMS patients in order to identify genomic regions associated with the severity of clinical symptoms. This study will lead to better diagnosis and to the identification of new therapeutic targets.
Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder with non-specific clinical features. The main symptoms are hypotonia, intellectual disability (ID), absent or delayed speech together with minor dysmorphic features. More than half of the patients exhibit autism spectrum disorders (ASD).
PMS is a contiguous gene syndrome resulting from deletion of the distal long arm of chromosome 22. The type and the size of the deletion can vary from one patient to another. In the vast majority of the cases, the deletion is de novo.
There is a gradient of severity in PMS. Some patients have difficulty to walk or may have a severe intellectual disability while other patients can speak and go to high school. The size of the deletion seems to contribute to the presence of some features (speech problems are more frequent in patients with large deletions). In contrast, seizures, hypotonia, birth weight, and gestational age at birth do not seem to correlate with deletion size.
Among the genes located at 22q13, we previously identified deleterious de novo mutations of the SHANK3 gene in patients with ASD and ID. SHANK3 codes for a synaptic scaffolding protein that plays an important role in the formation of dendrites and glutamatergic synapses. While SHANK3 has been extensively studied as a candidate gene for the neurological symptoms of PMS, it is clear that many other genes in the region are involved in the pathogenesis of PMS.
The genetic and phenotypic diversity of patients with PMS in Europe
In order to identify the factors that can modulate the severity of the syndrome, we aim at analyzing the genotype-phenotype relationship in all patients with PMS in Europe. Instead of focusing on the size of the 22q13 deletion, we want to analyze the whole genome of all patients with PMS.
Cellular and mouse models of PMS
In order to identify the causative mechanisms and the main neuronal circuits involved in PMS, we are currently studying cellular and mouse models of the syndrome. Our cellular models consist of neurons derived from induced pluripotent stem cells (iPSC) of patients with PMS or ASD carrying a de novo SHANK3 mutation. Our mouse models are based on mice lacking the SHANK3 gene.
Foundations and collaborative groups
- French Association of the Phelan-McDermid syndrome
- Phelan-McDermid Syndrome Foundation, USA
- Phelan-McDermid Syndrome Foundation, UK
- Italian Association of the Phelan-McDermid syndrome
- European consortium EU-AIMS
- Association Téhani et les enfants Phelan-McDermid, France
- USA (New Orleans): Dr Katy Phelan, Tulane University
- France (Paris): Pr Richard Delorme, Dr Anna Maruani, Centre d’excellence pour l’autisme et les trouble du neurodéveloppement (InovAND), CHU Hôpital Robert-Debré
- France (Paris): Pr Anne Claude Tabet, Service de cytogénétique, CHU Hôpital Robert-Debré
- France (Paris): Pr Thierry Bienvenu, Service de génétique moléculaire, CHU Paris Centre, Hôpital Cochin
- France (Nîmes): Pr Serge Lumbroso, CHU of Nîmes
- France (Angers): Pr Dominique Bonneau, CHU of Angers
- France (Clermont-Ferrand): Dr Christine Francannet, CHU of Clermont-Ferrand
- Belgium (Louvain): Pr Hilde Van Esch, University of Louvain
- Denmark (Odense): Dr Christina Fagerberg, Hôpital universitaire of Odense
- Netherlands (Groningen): Pr Conny van Ravenswaaij-Arts: email@example.com
- Germany (Ulm): Dr Sarah Jesse: firstname.lastname@example.org & Michael Schoen: email@example.com, Universitäts- und Rehabilitationskliniken Ulm
- UK (London): Eva Loth: firstname.lastname@example.org, Institute of Psychiatry, King’s College
- Italy (Milan): Stefano D’Arrigo, Istituto Neurologico Carlo Besta: Arrigo@istituto-besta.it
- Italy (Pisa): Filippo Muratori & Filippo Santorelli: email@example.com, firstname.lastname@example.org, Istituto Stella Maris
- Italy (Rome): Pr Marcella Zollino: email@example.com, Università Cattolica del Sacro Cuore
- Sicilia (Troina): Dr Maurizio Elia: firstname.lastname@example.org, Ospedale Oasi di Troina
- Germany (Ulm): Pr Tobias Boeckers: email@example.com, University of Ulm
- Italy (Milan): Dr Carlo Sala, University of Milan
- Italy (Milan): Dr Chiara Verpelli, University of Milan
- France (Évry): Dr Alexandra Benchoua, Institut des cellules souches pour le traitement et l’étude des maladies monogéniques (I-Stem)
- France (Paris): Dr David DiGregorio, Pasteur Institute
- France (Paris): Dr Laure Rondi-Reig, Institute of Biology Paris-Seine
Please visit the Frontiers Research Topics on Shankopathies.
About SHANK2 disorders? Check the website of the recent SHANK2 Foundation! Register your child in the SHANK2 Patient Registry and help it grows.
Our recent papers on the Phelan-McDermid syndrome and SHANK3:
A framework to identify contributing genes in patients with Phelan-McDermid syndrome
Anne-Claude Tabet, Thomas Rolland et al.