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Am J Hum Genet. 2019 Jan 3;104(1):164-178. doi: 10.1016/j.ajhg.2018.11.007. Epub 2018 Dec 20.

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.

Collaborators (167)

Adams DR, Alejandro ME, Allard P, Azamian MS, Bacino CA, Balasubramanyam A, Barseghyan H, Batzli GF, Beggs AH, Behnam B, Bican A, Bick DP, Birch CL, Bonner D, Boone BE, Bostwick BL, Briere LC, Brown DM, Brush M, Burke EA, Burrage LC, Chen S, Clark GD, Coakley TR, Cogan JD, Cooper CM, Cope H, Craigen WJ, D'Souza P, Davids M, Dayal JG, Dell'Angelica EC, Dhar SU, Dillon A, Dipple KM, Donnell-Fink LA, Dorrani N, Dorset DC, Douine ED, Draper DD, Eckstein DJ, Emrick LT, Eng CM, Eskin A, Esteves C, Estwick T, Ferreira C, Fogel BL, Friedman ND, Gahl WA, Glanton E, Godfrey RA, Goldstein DB, Gould SE, Gourdine JF, Groden CA, Gropman AL, Haendel M, Hamid R, Hanchard NA, Handley LH, Herzog MR, Holm IA, Hom J, Howerton EM, Huang Y, Jacob HJ, Jain M, Jiang YH, Johnston JM, Jones AL, Kohane IS, Krasnewich DM, Krieg EL, Krier JB, Lalani SR, Lau CC, Lazar J, Lee BH, Lee H, Levy SE, Lewis RA, Lincoln SA, Lipson A, Loo SK, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Markello TC, Marom R, Martínez-Agosto JA, Marwaha S, May T, McConkie-Rosell A, McCormack CE, McCray AT, Might M, Moretti PM, Morimoto M, Mulvihill JJ, Murphy JL, Muzny DM, Nehrebecky ME, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Orange JS, Pallais JC, Palmer CGS, Papp JC, Parker NH, Pena LDM, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Reuter CM, Robertson AK, Rodan LH, Rosenfeld JA, Sampson JB, Samson SL, Schoch K, Schroeder MC, Scott DA, Sharma P, Shashi V, Signer R, Silverman EK, Sinsheimer JS, Smith KS, Spillmann RC, Splinter K, Stoler JM, Stong N, Sullivan JA, Sweetser DA, Tifft CJ, Toro C, Tran AA, Urv TK, Valivullah ZM, Vilain E, Vogel TP, Wahl CE, Walley NM, Walsh CA, Ward PA, Waters KM, Westerfield M, Wise AL, Wolfe LA, Worthey EA, Yamamoto S, Yang Y, Yu G, Zastrow DB, Zheng A.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Department of Pediatrics, CHU Sainte-Justine Research Center and University of Montreal, Montreal, QC H3T 1C5, Canada.
3
Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
4
Department of Pediatrics and Neurobiology, Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC 27710, USA.
5
Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
6
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
7
Human Genetics Department, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
8
GeneDx, Gaithersburg, MD 20877, USA.
9
Unidad de Genética, Hospital Universitario i Politècnic La Fe, 106, 46026 Valencia, Spain.
10
Neuroscience Research Australia (NeuRA), University of New South Wales, Sydney, NSW 2031, Australia; New South Wales Health Pathology, Randwick, NSW 2217, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW 2031, Australia.
11
Neuroscience Research Australia (NeuRA), University of New South Wales, Sydney, NSW 2031, Australia.
12
New South Wales Health Pathology, Randwick, NSW 2217, Australia.
13
Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW 2031, Australia.
14
North East Thames Regional Genetics service, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
15
Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center, 3584 EA Utrecht, the Netherlands.
16
Department of Clinical Genetics, Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands.
17
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK; Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
18
Department of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA.
19
Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
20
Centre de Génétique, Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est et FHU TRANSLAD, CHU Dijon, 21079 Dijon, France.
21
AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge CB2 0AA, UK.
22
Department of Pediatrics and Division of Human Genetics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA 19104, USA.
23
Department of Pediatrics, CHU Sainte-Justine Research Center and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address: p.campeau@umontreal.ca.

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.

KEYWORDS:

Bafopathy; developmental delay; dysmorphisms; genotype-phenotype correlation; intellectual disability; neurodevelopmental disorder; speech delay; transcriptome

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