Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Bosch E, Popp B, Güse E, Skinner C, van der Sluijs PJ, Maystadt I, Pinto AM, Renieri A, Bruno LP, Granata S, Marcelis C, Baysal Ö, Hartwich D, Holthöfer L, Isidor B, Cogne B, Wieczorek D, Capra V, Scala M, De Marco P, Ognibene M, Jamra RA, Platzer K, Carter LB, Kuismin O, van Haeringen A, Maroofian R, Valenzuela I, Cuscó I, Martinez-Agosto JA, Rabani AM, Mefford HC, Pereira EM, Close C, Anyane-Yeboa K, Wagner M, Hannibal MC, Zacher P, Thiffault I, Beunders G, Umair M, Bhola PT, McGinnis E, Millichap J, van de Kamp JM, Prijoles EJ, Dobson A, Shillington A, Graham BH, Garcia EJ, Galindo MK, Ropers FG, Nibbeling EA, Hubbard G, Karimov C, Goj G, Bend R, Rath J, Morrow MM, Millan F, Salpietro V, Torella A, Nigro V, Kurki M, Stevenson RE, Santen GW, Zweier M, Campeau PM, Severino M, Reis A, Accogli A, Vasileiou G (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 25

Article Number: 100950

Journal Issue: 11

DOI: 10.1016/j.gim.2023.100950

Abstract

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.

Authors with CRIS profile

Involved external institutions

Universität Leipzig Germany (DE) Finnish Institute for Molecular Medicine (FIMM) / Suomen Molekyylilääketieteen Instituutti Finland (FI) Azienda ospedaliero-universitaria Senese Italy (IT) Cincinnati Children's Hospital Medical Center United States (USA) (US) Northwestern University United States (USA) (US) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Istituto Giannina Gaslini Italy (IT) Keck School of Medicine of USC United States (USA) (US) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) Centre Hospitalier Universitaire Sainte-Justine, CHU Sainte-Justine Canada (CA) Leiden University Medical Center Netherlands (NL) Berliner Institut für Gesundheitsforschung in der Charité / Berlin Institute of Health at Charité (BIH) Germany (DE) Vestische Kinder- und Jugendklinik Datteln Germany (DE) Free University Medical Center / VU Medisch Centrum Netherlands (NL) University College London (UCL) United Kingdom (GB) Columbia University Irving Medical Center (CUIMC) United States (USA) (US) GeneDX United States (USA) (US) Children's Hospital of Eastern Ontario (CHEO) / Centre hospitalier pour enfants de l'est de l'Ontario Canada (CA) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Indiana University – Purdue University Indianapolis United States (USA) (US) University of California Los Angeles (UCLA) United States (USA) (US) Oulu University Hospital Finland (FI) University of Zurich / Universität Zürich (UZH) Switzerland (CH) Universitätsmedizin der Johannes Gutenberg-Universität Mainz Germany (DE) University of Michigan United States (USA) (US) Greenwood Genetic Center United States (USA) (US) PreventionGenetics United States (USA) (US) Children's Mercy Hospital United States (USA) (US) Ann & Robert H. Lurie Children's Hospital of Chicago United States (USA) (US) St. Jude Children’s Research Hospital United States (USA) (US) Université de Nantes France (FR) Telethon Institute of Genetics and Medicine (TIGEM) Italy (IT) University of Arizona United States (USA) (US) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) Universitätsklinikum Düsseldorf Germany (DE) ​King Abdulaziz Medical City Saudi Arabia (SA) Kleinwachau - Sächsisches Epilepsiezentrum Radeberg gGmbH Germany (DE) Levine Children’s Hospital United States (USA) (US) University of Genova / Università degli Studi di Genova Italy (IT)

How to cite

APA:

Bosch, E., Popp, B., Güse, E., Skinner, C., van der Sluijs, P.J., Maystadt, I.,... Vasileiou, G. (2023). Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals. Genetics in Medicine, 25(11). https://doi.org/10.1016/j.gim.2023.100950

MLA:

Bosch, Elisabeth, et al. "Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals." Genetics in Medicine 25.11 (2023).

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