Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.
Journal Article (Journal Article)
SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
- Machol, K; Rousseau, J; Ehresmann, S; Garcia, T; Nguyen, TTM; Spillmann, RC; Sullivan, JA; Shashi, V; Jiang, Y-H; Stong, N; Fiala, E; Willing, M; Pfundt, R; Kleefstra, T; Cho, MT; McLaughlin, H; Rosello Piera, M; Orellana, C; Martínez, F; Caro-Llopis, A; Monfort, S; Roscioli, T; Nixon, CY; Buckley, MF; Turner, A; Jones, WD; van Hasselt, PM; Hofstede, FC; van Gassen, KLI; Brooks, AS; van Slegtenhorst, MA; Lachlan, K; Sebastian, J; Madan-Khetarpal, S; Sonal, D; Sakkubai, N; Thevenon, J; Faivre, L; Maurel, A; Petrovski, S; Krantz, ID; Tarpinian, JM; Rosenfeld, JA; Lee, BH; Undiagnosed Diseases Network, ; Campeau, PM
- January 3, 2019
Volume / Issue
- 104 / 1
Start / End Page
- 164 - 178
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)
- United States