Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals.
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Bosch Elisabeth, Popp Bernt, Güse Esther, Skinner Cindy, van der Sluijs Pleuntje J, Maystadt Isabelle, Pinto Anna Maria, Renieri Alessandra, Bruno Lucia Pia, Granata Stefania, Marcelis Carlo, Baysal Özlem, Hartwich Dewi, Holthöfer Laura, Isidor Bertrand, Cogne Benjamin, Wieczorek Dagmar, Capra Valeria, Scala Marcello, De Marco Patrizia, Ognibene Marzia, Jamra Rami Abou, Platzer Konrad, Carter Lauren B, Kuismin Outi, van Haeringen Arie, Maroofian Reza, Valenzuela Irene, Cuscó Ivon, Martinez-Agosto Julian A, Rabani Ahna M, Mefford Heather C, Pereira Elaine M, Close Charlotte, Anyane-Yeboa Kwame, Wagner Mallory, Hannibal Mark C, Zacher Pia, Thiffault Isabelle, Beunders Gea, Umair Muhammad, Bhola Priya T, McGinnis Erin, Millichap John, van de Kamp Jiddeke M, Prijoles Eloise J, Dobson Amy, Shillington Amelle, Graham Brett H, Garcia Evan-Jacob, Galindo Maureen Kelly, Ropers Fabienne G, Nibbeling Esther A R, Hubbard Gail, Karimov Catherine, Goj Guido, Bend Renee, Rath Julie, Morrow Michelle M, Millan Francisca, Salpietro Vincenzo, Torella Annalaura, Nigro Vincenzo, Kurki Mitja, Stevenson Roger E, Santen Gijs W E, Zweier Markus, Campeau Philippe M, Severino Mariasavina, Reis André, Accogli Andrea, Vasileiou Georgia
Аннотация
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.