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

Autor:	Bosch E; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Popp B; Berlin Institute of Health at Charitè, Universitätsklinikum Berlin, Centre of Functional Genomics, Berlin, Germany; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Güse E; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Skinner C; Greenwood Genetic Center, Greenwood, SC., van der Sluijs PJ; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Maystadt I; Center for Human Genetics, Institute of Pathology and Genetics, Gosselies, Belgium., Pinto AM; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy., Renieri A; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics Unit, University of Siena, Siena, Italy., Bruno LP; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy., Granata S; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics Unit, University of Siena, Siena, Italy., Marcelis C; Human Genetics department, Radboud university medical center, Nijmegen, The Netherlands., Baysal Ö; Human Genetics department, Radboud university medical center, Nijmegen, The Netherlands., Hartwich D; Institute of Human Genetics - University Medical Center of the Johannes Gutenberg University Mainz, Germany., Holthöfer L; Institute of Human Genetics - University Medical Center of the Johannes Gutenberg University Mainz, Germany., Isidor B; Nantes Université, CHU de Nantes, Service de Génétique médicale, Nantes, France; Nantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France., Cogne B; Nantes Université, CHU de Nantes, Service de Génétique médicale, Nantes, France; Nantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France., Wieczorek D; Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Capra V; Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Scala M; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., De Marco P; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Ognibene M; Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Jamra RA; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Platzer K; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Carter LB; Department of Pediatrics, Division of Medical Genetics, Levine Children's Hospital, Atrium Health, Charlotte, NC., Kuismin O; Department of Clinical Genetics, Research Unit of Clinical Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland., van Haeringen A; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Maroofian R; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom., Valenzuela I; Department of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain; Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain., Cuscó I; Department of Clinical and Molecular Genetics, University Hospital Vall d'Hebron, Barcelona, Spain; Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain., Martinez-Agosto JA; Departments of Human Genetics, Pediatrics, and Psychiatry, UCLA David Geffen School of Medicine, Los Angeles, CA., Rabani AM; Department of Pediatrics & Institute for Precision Health, UCLA David Geffen School of Medicine, Los Angeles, CA., Mefford HC; Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, TN., Pereira EM; Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY., Close C; Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY., Anyane-Yeboa K; Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY., Wagner M; Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Health System, University of Michigan, Ann Arbor, MI., Hannibal MC; Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan Health System, University of Michigan, Ann Arbor, MI., Zacher P; Epilepsy Center Kleinwachau, Radeberg, Germany., Thiffault I; Department of Pediatrics and Pathology, Genomic Medicine Center, Children's Mercy Kansas City and Children's Mercy Research Institute, Kansas City, MO., Beunders G; Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands., Umair M; Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, MNGHA, Riyadh, Saudi Arabia; Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan., Bhola PT; Department of Genetics, Children's Hospital of Eastern Ontario (CHEO), Ottawa, Canada., McGinnis E; Division of Neurology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL., Millichap J; Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL., van de Kamp JM; Department of Human Genetics, Amsterdam UMC, location VU Medical Center, Amsterdam, The Netherlands., Prijoles EJ; Greenwood Genetic Center, Greenwood, SC., Dobson A; Greenwood Genetic Center, Greenwood, SC., Shillington A; Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH., Graham BH; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN., Garcia EJ; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN., Galindo MK; Department of Pediatrics, University of Arizona, Tucson, AZ., Ropers FG; Willem-Alexander Children's Hospital, Department of Pediatrics, Leiden University Medical Center, The Netherlands., Nibbeling EAR; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Hubbard G; Department of Medical Genetics, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA., Karimov C; Department of Medical Genetics, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA., Goj G; Vestische Kinder- und Jugendklinik, Datteln, Germany., Bend R; PreventionGenetics, Part of Exact Sciences, Marshfield, WI., Rath J; PreventionGenetics, Part of Exact Sciences, Marshfield, WI., Morrow MM; GeneDx, Gaithersburg, MD., Millan F; GeneDx, Gaithersburg, MD., Salpietro V; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, United Kingdom; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy., Torella A; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli,' Naples, Italy., Nigro V; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli,' Naples, Italy., Kurki M; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA., Stevenson RE; Greenwood Genetic Center, Greenwood, SC., Santen GWE; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands., Zweier M; Institute of Medical Genetics, University of Zürich, Schlieren-Zurich, Switzerland., Campeau PM; Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, QC, Canada., Severino M; Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Reis A; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Centre for Rare Diseases Erlangen (ZSEER), Erlangen, Germany., Accogli A; Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre; Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, QC, Canada., Vasileiou G; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Centre for Rare Diseases Erlangen (ZSEER), Erlangen, Germany. Electronic address: georgia.vasileiou@uk-erlangen.de.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2023 Nov; Vol. 25 (11), pp. 100950. Date of Electronic Publication: 2023 Aug 05.
DOI:	10.1016/j.gim.2023.100950
Abstrakt:	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. Competing Interests: Conflict of Interest Renee Bend and Julie Rath are employees of PreventionGenetics, part of Exact Sciences. Michelle M. Morrow and Francisca Millan are employees of GeneDx, LLC. All other authors declare no conflicts of interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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