Pathogenic variants in SMARCA5 , a chromatin remodeler, cause a range of syndromic neurodevelopmental features

Abstract

Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

A national diagnostic framework for patients with ultra-rare disorders: molecular genetic findings using phenotypic and sequencing data

“…In SMARCA5, a gene coding for a chromatin remodeler, we identi ed de novo variants in two patients with neurodevelopmental delay and similar dysmorphic features. The phenotypegene association was strengthened by the identi cation of ten additional cases from other cohorts, and rescue experiments with wildtype transcripts in Drosophila suggested a hypomorphic effect of the variants 47 . In another individual with learning disabilities, autism, dystonia, and intention tremor, we identi ed a de novo missense variant in KCNN2, a small-conductance calcium-activated potassium channel.…”

“…Fifteen genes have subsequently reached DGG status. We brie y describe a few exemplary cases below, most of which have already been published in detail elsewhere [43][44][45][46][47][48][49][50][51][52] , and provide a comprehensive list of all patients in the Supplemental Material. In SMARCA5, a gene coding for a chromatin remodeler, we identi ed de novo variants in two patients with neurodevelopmental delay and similar dysmorphic features.…”

The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme

“…Among these genes, 90% (46/51) are implicated in cancer ( Table S2 ), including seven involved in glioblastoma pathogenesis, such as Polypyrimidine tract binding protein 2 ( PTBP2 ), encoding a splicing factor aberrantly overexpressed in GBM [ 45 ] and NOP2/Sun RNA methyltransferase 6 ( NSUN6 ) encoding the RNA 5-methyl cytosine (5mC) transferase that regulates the glioblastoma response to temozolomide [ 46 ]. Surprisingly, 33% of them (17/51) are genes mutated in children with neurodevelopmental disorders (NDDs; Table S2 ), including the Activator of transcription and developmental regulator AUTS2 ( AUTS2 ; MIM 607270) [ 47 ], SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 ( SMARCA5 , MIM 603375) [ 48 ], KAT8 regulatory NSL complex subunit 1 ( KANSL1 ; MIM 612452) [ 49 ], and Lysine methyltransferase 2A ( KMT2A; MIM 159555) [ 50 ] that are NDD chromatin remodeling genes (KW:0991; Figure 4 F; Table S2 ) as KDM5C [ 29 , 31 ].…”

Mammalian Resilience Revealed by a Comparison of Human Diseases and Mouse Models Associated With DNA Helicase Deficiencies

“…Only a minor fraction of SMARCA5 can bind to chromatin and translocate the post-translational modified nucleosome, while the majority of SMARCA5 is highly mobile ( Erdel et al, 2010 ). De novo or rare heterozygous variants of SMARCA5 in 12 patients were found to cause a neurodevelopmental syndrome with recurrent dysmorphic features, such as postnatal short stature associated with mild developmental delay and microcephaly ( Li et al, 2021 ).…”