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

• DOI: 10.1016/j.gim.2023.100950
• Publication Date: 2023-08-05T02:11:03Z
• Authors: Elisabeth Bosch; Bernt Popp; Esther Güse; Cindy Skinner; Pleuntje J. van d...; Isabelle Maystadt; Anna Maria Pinto; Alessandra Renieri; Lucia Pia Bruno; Stefania Granata; Carlo Marcelis; Özlem Baysal; Dewi Hartwich; Laura Holthöfer; Bertrand Isidor; Benjamin Cogne; Dagmar Wieczorek; Valeria Capra; Marcello Scala; Patrizia De Marco; Marzia Ognibene; Rami Abou Jamra; Konrad Platzer; Lauren B. Carter; Outi Kuismin; Arie van Haeringen; Reza Maroofian; Irene Valenzuela; Ivon Cuscó; Julian A. Martine...; Ahna M. Rabani; Heather C. Mefford; Elaine M. Pereira; Charlotte Close; Kwame Anyane-Yeboa; Mallory Wagner; Mark C. Hannibal; Pia Zacher; Isabelle Thiffault; Gea Beunders; Muhammad Umair; Priya T. Bhola; Erin McGinnis; John Millichap; Jiddeke M. van de...; Eloise J. Prijoles; Amy Dobson; Amelle Shillington; Brett H. Graham; Evan-Jacob Garcia; Maureen Kelly Gal...; Fabienne G. Ropers; Esther A.R. Nibbe...; Gail Hubbard; Catherine Karimov; Guido Goj; Renee Bend; Julie Rath; Michelle M. Morrow; Francisca Millan; Vincenzo Salpietro; Annalaura Torella; Vincenzo Nigro; Mitja Kurki; Roger E. Stevenson; Gijs W.E. Santen; Markus Zweier; Philippe M. Campeau; Mariasavina Severino; André Reis; Andrea Accogli; Georgia Vasileiou
• Keywords: NDD; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Nicolaides-Baraitser syndrome; Micrognathism; 610; Radboud University Medical Center; SMARCC2; Facies; neurodevelopmental disorder; 3. Good health; BAF; BAFopathy; Coffin-Siris syndrome; NDD; SMARCC2;; DNA-Binding Proteins; Phenotype; Neurodevelopmental Disorders; Face; Intellectual Disability; BAF; BAFopathy; Coffin-Siris syndrome; NDD; SMARCC2; Humans; BAFopathy; Coffin-Siris syndrome; Abnormalities, Multiple; BAF; BAF; BAFopathy; Coffin-Siris syndrome; NDD; Nicolaides-Baraitser syndrome; SMARCC2; neurodevelopmental disorder; Transcription Factors

ABSTRACTPURPOSECoffin-Siris and Nicolaides-Baraitser syndromes, are recognisable neurodevelopmental disorders caused by germline variants in BAF complex subunits. TheSMARCC2BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.METHODSClinical symptoms for 41 novel and 24 previously published cases were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlation, molecular data were standardized and grouped into non-truncating and likely gene-disrupting variants (LGD). Missense variant protein expression and BAF subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.RESULTSNeurodevelopmental 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, while non-truncating variants were mostlyde novoand presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms.In vitrotesting showed decreased protein expression for N-terminal missense variants similar to LGD.CONCLUSIONThis study improvedSMARCC2variant classification and identified discernibleSMARCC2-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.