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

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 the SHANK3 gene. SHANK3 is 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 inherited SHANK3 deletion 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.

SUBMITTER: Tabet AC

PROVIDER: S-EPMC5677962 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Tabet Anne-Claude AC Rolland Thomas T Ducloy Marie M Lévy Jonathan J Buratti Julien J Mathieu Alexandre A Haye Damien D Perrin Laurence L Dupont Céline C Passemard Sandrine S Capri Yline Y Verloes Alain A Drunat Séverine S Keren Boris B Mignot Cyril C Marey Isabelle I Jacquette Aurélia A Whalen Sandra S Pipiras Eva E Benzacken Brigitte B Chantot-Bastaraud Sandra S Afenjar Alexandra A Héron Delphine D Le Caignec Cédric C Beneteau Claire C Pichon Olivier O Isidor Bertrand B David Albert A El Khattabi Laila L Kemeny Stephan S Gouas Laetitia L Vago Philippe P Mosca-Boidron Anne-Laure AL Faivre Laurence L Missirian Chantal C Philip Nicole N Sanlaville Damien D Edery Patrick P Satre Véronique V Coutton Charles C Devillard Françoise F Dieterich Klaus K Vuillaume Marie-Laure ML Rooryck Caroline C Lacombe Didier D Pinson Lucile L Gatinois Vincent V Puechberty Jacques J Chiesa Jean J Lespinasse James J Dubourg Christèle C Quelin Chloé C Fradin Mélanie M Journel Hubert H Toutain Annick A Martin Dominique D Benmansour Abdelamdjid A Leblond Claire S CS Toro Roberto R Amsellem Frédérique F Delorme Richard R Bourgeron Thomas T

NPJ genomic medicine 20171023

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 the <i>SHANK3</i> gene. <i>SHANK3</i> is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we invest ...[more]

PMID: 29263841

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Project description:BackgroundPhelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability.MethodsWe used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison.ResultsWe found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size.ConclusionsThis study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.

Dataset Information

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

Publications

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

Similar Datasets

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