Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder with extensive clinical and genetic heterogeneity that is still poorly understood. The phenotype includes hypotonia, delayed psychomotor development, intellectual disability of varying severity, and consistent language impairment ranging from delayed to absent speech. Autism spectrum disorders are present in 60-80% of patients, and other comorbidities may be present. The major candidate gene for PMS is SHANK3, which encodes a scaffolding protein in the dense postsynaptic region of glutamatergic synapses. Its loss of function is caused by deletions in the distal region of chromosome 22, 22q13.3, or by intragenic genomic variants. Several studies, including the one conducted by our team, have shown that part of the variability in the phenotype is related to the size of the 22q13.3 deletion. However, two patients with a deletion of similar size or an identical point variation in SHANK3 can have phenotypes of very variable severity.
The existence of additional genomic variants not identified by standard diagnostic techniques, particularly DNA chip chromosomal analysis (ACPA), which may act as modulating elements of the phenotype, has been suggested.
The limitations of the proposed studies are the highly heterogeneous genomic tools used (variable DNA chip design in terms of probe distribution and resolution) and the often imprecise phenotypes. Our study will bring together a large number of SPM patients (related to a 22q13.3 deletion or a variation of the SHANK3 gene) as well as their parents and possible relatives (first or second degree of the patient), very well phenotyped and explored by complete genome sequencing on the same sequencing platform.
Patient diagnosed with Phelan-McDermid syndrome as part of the etiological assessment of a neurodevelopmental disorder, regardless of age (and their parents, siblings, and grandparents).
For patients: identification of a deletion affecting SHANK3 or a specific, deleterious genetic variation in SHANK3.
Affiliation to a social security scheme or beneficiary.
Signature of the project consent form by the participant (if an adult) or by both legal guardians (if the participant is a minor or an adult under guardianship).
None
Single group
SHANK3 mutation
Diagnostic testblood sampling for diagnostic test
Better Understanding the Clinical Variability of the Phelan-McDermid Syndrome
* Through precise characterization of the variation affecting the SHANK3 gene: mutation type, location of the variant, impact on the protein, and the specific SHANK3 isoform involved. * By identifying additional genetic variations (outside of SHANK3) that may contribute to associated conditions such as epilepsy, cardiopathy, or gastrointestinal disorders. * In cases of 22q13.3 deletions that include SHANK3-and therefore lead to a neurodevelopmental disorder-when additional genes are also affected by the deletion, better understanding the contribution of each of these genes to the presence and severity of associated clinical features.
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