The relationship between SHANK3 and autosomal dominant Phelan-McDermid syndrome was first suggested in 2001, when a balanced translocation disrupting the SHANK3 gene was reported (Bonaglia et al., PMID: 11431708). The first SHANK3 sequence variants were reported in 2007 (Durand et al., PMID: 17173049). SHANK3 encodes a scaffolding protein in the postsynaptic density of glutamatergic synapses and plays a critical role in synaptic function. Phelan-McDermid syndrome can be caused by defects in SHANK3 or by large deletions involving additional genes (also known as 22q13.3 deletion syndrome) that are responsible for the varied phenotype and severity amongst individuals. The syndrome is characterized by neonatal hypotonia, global developmental delay, intellectual disability, severely delayed or absent speech, autism spectrum disorder, seizures, neuroimaging abnormalities, and mild facial dysmorphism.
Thirteen variants (frameshift, nonsense, and missense) that have been reported in 14 probands in three publications (PMIDs: 23758760, 25188300, 29719671) are included in this curation. Variants occurred de novo in all instances in which parental DNA was available. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is haploinsufficiency. This gene-disease relationship is also supported by in vitro functional assays, rescue experiments and animal models.
In summary, there is definitive evidence supporting the relationship between SHANK3 and autosomal dominant Phelan-McDermid syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 12, 2018 (SOP Version 6). As of October 2025, this record underwent administrative updates to include edits to the evidence summary and update scoring to be consistent with SOP Version 11. No new evidence was added, and the classification remains the same.
The relationship between SHANK3 and autosomal dominant Phelan-McDermid syndrome was first suggested in 2001, when a balanced translocation disrupting the SHANK3 gene was reported (Bonaglia et al., PMID: 11431708). The first SHANK3 sequence variants were reported in 2007 (Durand et al., PMID: 17173049). SHANK3 encodes a scaffolding protein in the postsynaptic density of glutamatergic synapses and plays a critical role in synaptic function. Phelan-McDermid syndrome can be caused by defects in SHANK3 or by large deletions involving additional genes (also known as 22q13.3 deletion syndrome) that are responsible for the varied phenotype and severity amongst individuals. The syndrome is characterized by neonatal hypotonia, global developmental delay, intellectual disability, severely delayed or absent speech, autism spectrum disorder, seizures, neuroimaging abnormalities, and mild facial dysmorphism.
Thirteen variants (frameshift, nonsense, and missense) that have been reported in 14 probands in three publications (PMIDs: 23758760, 25188300, 29719671) are included in this curation. Variants occurred de novo in all instances in which parental DNA was available. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is haploinsufficiency. This gene-disease relationship is also supported by in vitro functional assays, rescue experiments and animal models.
In summary, there is definitive evidence supporting the relationship between SHANK3 and autosomal dominant Phelan-McDermid syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 12, 2018 (SOP Version 6). As of October 2025, this record underwent administrative updates to include edits to the evidence summary and update scoring to be consistent with SOP Version 11. No new evidence has been added, and the classification remains the same.
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