SMARCB1 was first reported in relation to autosomal dominant Coffin-Siris syndrome (CSS) in 2012 (PMID: 22426308). Coffin-Siris syndrome is characterized by intellectual disability, coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. Five missense variants and inframe deletions, including recurrent p.(Lys364del) and p.(Arg37His), reported in 20 probands in 6 publications (PMIDs: 22426308, 23815551, 23906836, 23929686, 25168959, 29907796) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is dominant-negative (PMID: 31759698).
This gene-disease relationship is also supported by animal and cell culture models (PMIDs: 31273213, 31759698). Mice with heterozygous disruption of Smarcb1 exhibit brain midline abnormalities like those seen in CSS individuals (PMID: 31273213). In human induced plurpotent stem cells genetically modified to harbor the recurrent inframe variant p.(Lys364del), neuron count and neurite outgrwoth are diminished, and gene expression is downregulated (PMID: 31759698).
In summary, there is definitive evidence to support the relationship between SMARCB1 and autosomal dominant Coffin-Siris 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 August 15, 2023 (SOP Version 9).
SMARCB1 was first reported in relation to autosomal dominant Coffin-Siris syndrome (CSS) in 2012 (PMID: 22426308). Coffin-Siris syndrome is characterized by intellectual disability, coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. Five missense variants and inframe deletions, including recurrent p.(Lys364del) and p.(Arg37His), reported in 20 probands in 6 publications (PMIDs: 22426308, 23815551, 23906836, 23929686, 25168959, 29907796) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is dominant-negative (PMID: 31759698).
This gene-disease relationship is also supported by animal and cell culture models (PMIDs: 31273213, 31759698). Mice with heterozygous disruption of Smarcb1 exhibit brain midline abnormalities like those seen in CSS individuals (PMID: 31273213). In human induced pluripotent stem cells genetically modified to harbor the recurrent inframe variant p.(Lys364del), neuron count and neurite outgrwoth are diminished, and gene expression is downregulated (PMID: 31759698).
In summary, there is definitive evidence to support the relationship between SMARCB1 and autosomal dominant Coffin-Siris 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 August 15, 2023 (SOP Version 9).
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