This report describes a newly defined neurodevelopmental syndrome associated with de novo or heterozygous (autosomal dominant) mutations in the SMARCA5 gene. SMARCA5 encodes a SWI/SNF protein that functions as a component of multiple chromatin remodeling complexes. There is a single orthologous gene in Drosophila, Iswi, for which multiple genetic reagents have been generated, including loss-of-function mutations, overexpression and RNAi targeting constructs, and alleles caused by insertional mutagenesis. Dmel\Iswi is also orthologous to the human gene SMARCA1.
Multiple UAS constructs of Hsap\SMARCA5 have been introduced into flies, including wild-type and variants associated with this disease. Variant(s) implicated in human disease tested (as transgenic human gene, SMARCA5): the R592Q and 268-319del variant forms of the human gene have been introduced into flies. Heterologous rescue (functional complementation) by the wild-type human gene has been demonstrated for neural loss-of-function phenotypes of Iswi; reduced or no rescue is effected by human genes carrying the disease-implicated variants.
Animals homozygous for a loss-of-function allele of Dmel\Iswi typically die during the second larval instalr; survivors to the third larval instar are substantially smaller than wild type and exhibit numerous neuroanatomy defects. Pan-neuronal knockdown of Iswi, effected by RNAi, allows survival to adulthood; adults exhibit smaller brain size, structural defects in the brain, and locomotor defects. Numerous physical and genetic interactions have been described for Iswi; see below and in the Iswi gene report.
[updated Jun. 2021 by FlyBase; FBrf0222196]
This syndrome encompasses core presentations of mild developmental delay, postnatal microcephaly, short stature, and mild facial dysmorphia (Li et al., 2021; pubmed:33980485; FBrf0248991).
The initial 12 individuals studied carried de novo or dominantly segregating rare heterozygous variants in the SMARCA5 gene (Li et al., 2021; pubmed:33980485; FBrf0248991).
The protein encoded by SMARCA5 is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities; they are components of chromatin remodeling complexes thought to regulate transcription of targeted genes by localized chromatin remodeling (alteration of DNA-nucleosome topology). [Gene Cards, SMARCA5; 2021.06.01]
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human SMARCA1 and SMARCA5 (1 Drosophila to 2 human). Dmel\Iswi shares 70-71% identity and 82-83% similarity with the human gene.
