Pathogenic variants inSMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features

Abstract

Intellectual disability (ID) encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for over 50% of the patients remains elusive. We describe mutations in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a novel neurodevelopmental disorder, identifying twelve 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 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.

The chromatin remodeler ISWI acts during Drosophila development to regulate adult sleep

“…Last, we recently characterized human mutations in SMARCA5 as a cause of a previously unidentified NDD, identifying 12 individuals with de novo or rare heterozygous variants ( 22 ). We generated fly lines of SMARCA5 with two patient mutations under UAS control ( UAS-SMARCA5 R592Q and UAS-SMARCA5 del268-319 ).…”

“…These results implicate a role for SMARCA5 in the development of normal human sleep regulation. It will be of great interest to assess sleep in patients with SMARCA5 mutations given our findings in flies and humans ( 22 ). Moreover, because developmental ISWI knockdown leads to sleep abnormalities in the adult fly, longitudinal patient sleep phenotyping may reveal sleep differences across the lifespan.…”

“…Mutations in the human ISWI homolog SMARCA1 have been implicated in diverse NDDs (19)(20)(21), and we have recently described a novel NDD caused by mutations in SMARCA5 (22). However, there has been no clinical characterization of sleep phenotypes arising from patient mutations in SMARCA1 or SMARCA5.…”

“…Across species, ISWI and its homologs are adenosine 5′-triphosphate-dependent chromatin remodelers that regulate the expression of genes important for neural stem cell proliferation and differentiation (13)(14)(15)(16)(17)(18). Rare variants in the human homologs of ISWI, SMARCA1 and SMARCA5, have been implicated in several NDDs (18)(19)(20)(21)(22). Moreover, large-scale genome-wide and exome sequencing studies on patient cohorts have shown that genetic factors contributing to NDDs converge on chromatin regulation pathways (23,24).…”

Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition

“…Smarca5 conditional knockout mice are reduced in size and have severe defects in progenitor proliferation resulting in forebrain hypoplasia or impaired postnatal growth of the cerebellum depending on the Cre-driver line used to ablate the gene (33,36). Indeed, the Smarca5 mouse models are representative of the phenotype in individuals with SMARCA5 germline pathogenic variants who present with developmental delay, short stature, and microcephaly (37). In contrast, progenitor differentiation is delayed in Smarca1 mutant mice (Ex6DEL) leading to increased neuronal production and mice with larger brains (38).…”