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Expanding the spectrum of BAF-related disorders: de novo variants in SMARCC2 cause a syndrome with intellectual disability and developmental delay

Expanding the spectrum of BAF-related disorders: de novo variants in SMARCC2 cause a syndrome with intellectual disability and developmental delay
Expanding the spectrum of BAF-related disorders: de novo variants in SMARCC2 cause a syndrome with intellectual disability and developmental delay

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.

Bafopathy, developmental delay, dysmorphisms, genotype-phenotype correlation, intellectual disability, neurodevelopmental disorder, speech delay, transcriptome
0002-9297
164-178
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Machol, Keren, Rousseau, Justine, Ehresmann, Sophie and Lee, Brendan H. , Undiagnosed Diseases Network (2019) Expanding the spectrum of BAF-related disorders: de novo variants in SMARCC2 cause a syndrome with intellectual disability and developmental delay. American Journal of Human Genetics, 104 (1), 164-178. (doi:10.1016/j.ajhg.2018.11.007).

Record type: Article

Abstract

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.

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More information

Accepted/In Press date: 14 November 2018
e-pub ahead of print date: 20 December 2018
Published date: 3 January 2019
Keywords: Bafopathy, developmental delay, dysmorphisms, genotype-phenotype correlation, intellectual disability, neurodevelopmental disorder, speech delay, transcriptome

Identifiers

Local EPrints ID: 429232
URI: http://eprints.soton.ac.uk/id/eprint/429232
ISSN: 0002-9297
PURE UUID: 6c38b3d0-ea99-4b0f-9c13-ccff09db5df5

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Date deposited: 22 Mar 2019 17:30
Last modified: 06 Oct 2020 22:45

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Contributors

Author: Keren Machol
Author: Justine Rousseau
Author: Sophie Ehresmann
Author: Thomas Garcia
Author: Thi Tuyet Mai Nguyen
Author: Rebecca C. Spillmann
Author: Jennifer A. Sullivan
Author: Vandana Shashi
Author: Yong hui Jiang
Author: Nicholas Stong
Author: Elise Fiala
Author: Marcia Willing
Author: Rolph Pfundt
Author: Tjitske Kleefstra
Author: Megan T. Cho
Author: Heather McLaughlin
Author: Monica Rosello Piera
Author: Carmen Orellana
Author: Francisco Martínez
Author: Alfonso Caro-Llopis
Author: Sandra Monfort
Author: Tony Roscioli
Author: Cheng Yee Nixon
Author: Michael F. Buckley
Author: Anne Turner
Author: Wendy D. Jones
Author: Peter M. van Hasselt
Author: Floris C. Hofstede
Author: Koen L.I. van Gassen
Author: Alice S. Brooks
Author: Marjon A. van Slegtenhorst
Author: Katherine Lachlan
Author: Jessica Sebastian
Author: Suneeta Madan-Khetarpal
Author: Desai Sonal
Author: Naidu Sakkubai
Author: Julien Thevenon
Author: Laurence Faivre
Author: Alice Maurel
Author: Slavé Petrovski
Author: Ian D. Krantz
Author: Jennifer M. Tarpinian
Author: Jill A. Rosenfeld
Author: Brendan H. Lee
Corporate Author: Undiagnosed Diseases Network

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