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[This corrects the article DOI: 10.1038/s41525-017-0035-2.].
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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.
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Autism spectrum disorders: heterogeneous genetic etiologies. Autism Spectrum Disorders (ASD) are neurodevelopmental diseases affecting around 1% of the general population. Symptoms appear early in the development, usually before 3 years of life. Clinical features are extremely heterogeneous as genetic etiologies that underlie ASD. Genetic findings are present in 25% of ASD patients especially in specific cellular pathways as neurodevelopment or synapse architecture. ASD appears to be the combination of several de novo or/and inherited deleterious genetic variants. Here we propose to discuss genetic findings in these disorders and see how genetic research is able to give new treatment for ASD.
Autisme : une maladie génétique hétérogène. L'autisme est la forme la plus sévère des troubles du spectre autistique qui touchent actuellement 1 % de la population générale et dont les symptômes apparaissent au cours des premières années de vie. Ces troubles très hétérogènes au plan clinique sont majoritairement causés par des anomalies génétiques hétérogènes et complexes survenant de novo ou héritées et dont les effets délétères peuvent se cumuler. Ces mutations génétiques touchent principalement des grandes voies cellulaires comme le neurodéveloppement et l'architecture synaptique. Le dépistage précoce, les interventions comportementales intensives, la poursuite des recherches génétiques permettront à l'avenir d'améliorer le pronostic encore sombre des troubles du spectre autistique.