Abstract
Original language | English |
---|---|
Article number | 100950 |
Journal | Genetics in medicine |
Volume | 25 |
Issue number | 11 |
DOIs | |
Publication status | Published - 1 Nov 2023 |
Keywords
- BAF
- BAFopathy
- Coffin-Siris syndrome
- NDD
- SMARCC2
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In: Genetics in medicine, Vol. 25, No. 11, 100950, 01.11.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals
AU - Bosch, Elisabeth
AU - Popp, Bernt
AU - Güse, Esther
AU - Skinner, Cindy
AU - van der Sluijs, Pleuntje J.
AU - Maystadt, Isabelle
AU - Pinto, Anna Maria
AU - Renieri, Alessandra
AU - Bruno, Lucia Pia
AU - Granata, Stefania
AU - Marcelis, Carlo
AU - Baysal, Özlem
AU - Hartwich, Dewi
AU - Holthöfer, Laura
AU - Isidor, Bertrand
AU - Cogne, Benjamin
AU - Wieczorek, Dagmar
AU - Capra, Valeria
AU - Scala, Marcello
AU - de Marco, Patrizia
AU - Ognibene, Marzia
AU - Jamra, Rami Abou
AU - Platzer, Konrad
AU - Carter, Lauren B.
AU - Kuismin, Outi
AU - van Haeringen, Arie
AU - Maroofian, Reza
AU - Valenzuela, Irene
AU - Cuscó, Ivon
AU - Martinez-Agosto, Julian A.
AU - Rabani, Ahna M.
AU - Mefford, Heather C.
AU - Pereira, Elaine M.
AU - Close, Charlotte
AU - Anyane-Yeboa, Kwame
AU - Wagner, Mallory
AU - Hannibal, Mark C.
AU - Zacher, Pia
AU - Thiffault, Isabelle
AU - Beunders, Gea
AU - Umair, Muhammad
AU - Bhola, Priya T.
AU - McGinnis, Erin
AU - Millichap, John
AU - van de Kamp, Jiddeke M.
AU - Prijoles, Eloise J.
AU - Dobson, Amy
AU - Shillington, Amelle
AU - Graham, Brett H.
AU - Garcia, Evan-Jacob
AU - Galindo, Maureen Kelly
AU - Ropers, Fabienne G.
AU - Nibbeling, Esther A. R.
AU - Hubbard, Gail
AU - Karimov, Catherine
AU - Goj, Guido
AU - Bend, Renee
AU - Rath, Julie
AU - Morrow, Michelle M.
AU - Millan, Francisca
AU - Salpietro, Vincenzo
AU - Torella, Annalaura
AU - Nigro, Vincenzo
AU - Kurki, Mitja
AU - Stevenson, Roger E.
AU - Santen, Gijs W. E.
AU - Zweier, Markus
AU - Campeau, Philippe M.
AU - Severino, Mariasavina
AU - Reis, André
AU - Accogli, Andrea
AU - Vasileiou, Georgia
N1 - Funding Information: The authors thank the individuals and their families for participating in this study. Furthermore, we are indebted to GeneDX for establishing contact with the clinicians. The authors I.M. A.R. D.W. V.C. O.K. G.W.E.S. A.R. and G.V. are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]. The authors acknowledge ERN-ITHACA for posting a call for a collaborative project, which led to the recruitment of SMARCC2 individuals. Also, we acknowledge TUDP for performing exome sequencing of Fam-21 with the Telethon project GSP15001. B.P. is supported by the Deutsche Forschungsgemeinschaft (DFG) through grant PO2366/2–1. A.R. received support from the German Federal Ministry of Research and Education (01GM1520A) as part of the Chromatin-Net Consortium. Conceptualization: A.A. G.V.; Data Curation: A.A. B.P. G.V.; Formal Analysis: E.B. B.P. M.S.; Investigation: E.B. E.G. B.P. G.V.; Methodology: E.B. B.P. G.V.; Project Administration: G.V.; Resources: M.Z. B.P. C.S. P.J. van der S. I.M. A.M.P. A.R. L.P.B. S.G. C.M. O.B. D.H. L.H. B.I. B.C. D.W. V.C. M.S. P.D.M. M.O. R.A.J. K.P. L.B.C. O.K. A. van H. R.M. I.V. I.C. J.A.M.-A. A.M.R. H.C.M. E.M.P. C.C. K.A.-Y. M.W. M.C.H. P.Z. I.T. G.B. M.U. P.T.B. E.M. J.M. J.M. van de K. E.J.P. A.D. A.S. B.H.G. E.-J.G. M.K.G. F.G.R. E.A.R.N. G.H. C.K. G.G. R.B. J.R. M.M.M. F.M. V.S. A.T. V.N. M.K. R.E.S. G.W.E.S. M.Z. P.M.C. M.S. A.R. A.A. G.V.; Software: N/A; Supervision: G.V.; Validation: E.B.; Visualization: E.B. B.P. A.A. G.V.; Writing-original draft: E.B. B.P. A.A. G.V.; Writing-review & editing: A.R. G.V. Legal guardians gave written informed consent for genetic and clinical data, including photos and brain images, to be published. This study follows the Declaration of Helsinki protocols and is approved by the ethics committees of the Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany (259_16 Bc), University of Leipzig Germany (224/16-ek and 402/16-ek), Leiden University Medical Center, Leiden, The Netherlands (G21.129), Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy (number of protocol 81/21), North Ostrobothnia's Hospital District (19.4.2021, Eettmk § 110), Greenwood Genetic Center, Self Regional Healthcare (Institutional Review Board (IRB) Number: Pro00085001), UMT - University of Management and Technology, Lahore, Pakistan {IRB Ref. Number: DLSBBC-2022-04}, Hospital vall d'Hebron (code C.0002416) and the Children's Mercy IRB (Study # 11120514). Funding Information: B.P. is supported by the Deutsche Forschungsgemeinschaft (DFG) through grant PO2366/2–1. A.R. received support from the German Federal Ministry of Research and Education (01GM1520A) as part of the Chromatin-Net Consortium. Publisher Copyright: © 2023 The Authors
PY - 2023/11/1
Y1 - 2023/11/1
N2 - Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.
AB - Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.
KW - BAF
KW - BAFopathy
KW - Coffin-Siris syndrome
KW - NDD
KW - SMARCC2
UR - http://www.scopus.com/inward/record.url?scp=85173555062&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.gim.2023.100950
DO - https://doi.org/10.1016/j.gim.2023.100950
M3 - Article
C2 - 37551667
SN - 1098-3600
VL - 25
JO - Genetics in medicine
JF - Genetics in medicine
IS - 11
M1 - 100950
ER -