SMARCA5 encodes the ATPase motor of the ISWI chromatin remodeler. SMARCA5 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2021 (Li et al., PMID: 33980485). Affected individuals exhibit mild developmental delay, intellectual disability (in 50%), failure to thrive, postnatal microcephaly, short stature, mild dysmorphic facial features and mild skeletal and limb abnormalities (PMID: 33980485). Other less frequent features may include hypotonia, behavioral abnormalities, and seizures.
Nine variants (7 missense and 2 in-frame deletions) reported in 10 probands in one publication (PMID: 33980485) are included in this curation. Most reported variants occur de novo. One variant is recurrent (p.Ile434_Leu435del), and several variants are located within or around the helicase domains. The mechanism of pathogenicity appears to be partial loss of function, based on the study of a missense variant and an in-frame variant in a Drosophila model (PMID: 33980485).
This gene-disease relationship is also supported by experimental evidence, including a non-mammalian model system, biochemical function and protein interactions. Neuro-specific knockdown of Iswi, the SMARCA5 ortholog in Drosophila, led to smaller brain size, structural deficits of the mushroom body, and impaired motor function (PMID: 33980485). Another member of the ISWI complex, BPTF, has been shown to interact with SMARCA5 (PMID: 22729083) and is involved in a neurodevelopmental disorder with overlapping features.
In summary, there is moderate evidence supporting the relationship between SMARCA5 and autosomal dominant complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 18, 2025 (SOP Version 11).
SMARCA5 encodes the ATPase motor of the ISWI chromatin remodeler. SMARCA5 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2021 (Li et al., PMID: 33980485). Affected individuals exhibit mild developmental delay, intellectual disability (in 50%), failure to thrive, postnatal microcephaly, short stature, mild dysmorphic facial features and mild skeletal and limb abnormalities (PMID: 33980485). Other less frequent features may include hypotonia, behavioral abnormalities, and seizures.
Nine variants (7 missense and 2 in-frame deletions) reported in 10 probands in one publication (PMID: 33980485) are included in this curation. Most reported variants occur de novo. One variant is recurrent (p.Ile434_Leu435del), and several variants are located within or around the helicase domains. The mechanism of pathogenicity appears to be partial loss of function, based on the study of a missense variant and an in-frame variant in a Drosophila model (PMID: 33980485).
This gene-disease relationship is also supported by experimental evidence, including a non-mammalian model system, biochemical function and protein interactions. Neuro-specific knockdown of Iswi, the SMARCA5 ortholog in Drosophila, led to smaller brain size, structural deficits of the mushroom body, and impaired motor function (PMID: 33980485). Another member of the ISWI complex, BPTF, has been shown to interact with SMARCA5 (PMID: 22729083) and is involved in a neurodevelopmental disorder with overlapping features.
In summary, there is moderate evidence supporting the relationship between SMARCA5 and autosomal dominant complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panels on June 18, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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