Multimodal genotype-phenotype analysis in SMARCB1-associated developmental disorders
Genetics in Medicine, vol. 28, pp. 102614
Abstract
PURPOSE: Variants in SMARCB1, encoding a core subunit of the BAF (ie, BRG/BRM-associated factor) chromatin remodeling complex, are associated with intellectual developmental disorders, particularly Coffin-Siris syndrome, although the genotype-phenotype spectrum remains incompletely defined. This study aims to assess the correlations between SMARCB1 variant location and phenotypic manifestations. METHODS: We analyzed 31 individuals with pathogenic or likely pathogenic SMARCB1 variants using multimodal approaches, integrating clinical, structural, and machine learning analyses. We predicted variant effects via 3-dimensional protein modeling, assessed facial similarity using GestaltMatcher, and conducted phenotype-driven genotype prediction using machine learning classifiers. RESULTS: Variants clustered within the N-terminal (winged-helix/SNF5) and C-terminal (αC-helix) regions. C-terminal Coffin-Siris syndrome variants were associated with more severe speech delay, microcephaly, and cleft palate, exhibiting stronger facial gestalt similarity. XGBoost achieved 96.7% accuracy in classifying variant location from phenotype alone. Although gestalt is a key feature delineating variants at the αC helix, overall clinical features have greater predictive power for N-terminal variants. CONCLUSION: Using detailed phenotyping and machine learning algorithms, we identified differences between individuals with N-terminus and C-terminus SMARCB1 variants. Our study underscored the importance of multimodal assessments for genotype-phenotype associations, suggesting that integrated modeling can provide insights into SMARCB1 variant effects and biological function, with the potential for improvement in diagnostic strategies.
Authors 26
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King's College London · Great Ormond Street Hospital · Great Ormond Street Hospital for Children NHS Foundation Trust
Affiliation as printed
Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom; Clinical Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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King's College London · The Francis Crick Institute
Affiliation as printed
Neural Stem Cell Biology Lab, The Francis Crick Institute, London, United Kingdom; Department of Medical and Molecular Genetics, School of Basic & Medical Biosciences, King's College London, London, United Kingdom
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, United Kingdom
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University of Bonn · University Hospital Bonn
Affiliation as printed
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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Belfast Health and Social Care Trust · Belfast City Hospital
Affiliation as printed
Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast Health & Social Care Trust, Belfast, Northern Ireland, United Kingdom
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Baylor College of Medicine · Texas Children's Hospital
Affiliation as printed
Department of Molecular and Human Genetics, Baylor College of Medicine, Genetics Service, Texas Children's Hospital, Houston, TX
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University of California San Diego · Rady Children's Hospital-San Diego
Affiliation as printed
Department of Pediatrics, University of California San Diego, Division of Dysmorphology and Genetics, Rady Children's Hospital San Diego, San Diego, CA
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University of British Columbia · BC Children's Hospital Research Institute
Affiliation as printed
Department of Medical Genetics and the British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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University of British Columbia · BC Children's Hospital Research Institute
Affiliation as printed
Department of Medical Genetics and the British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
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Northwick Park Hospital · St Mark's Hospital
Affiliation as printed
North West Thames Regional Genetics Service, NHS, Northwick Park & St Mark's Hospitals, London, Harrow, United Kingdom
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Centro Hospitalar Lisboa Norte · Hospital de Santa Maria
Affiliation as printed
Serviço de Genética Médica, Centro Hospitalar Universitário Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
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Inserm · Université de Bourgogne · CHU Dijon Bourgogne · Genomic and Immunotherapy Medical Institute · Centre de recherche Translationnelle en Médecine moléculaire
Affiliation as printed
Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France; Centre de Référence Maladies Rares "Anomalies du développement et syndromes malformatifs", Centre de Génétique, FHU-TRANSLAD et Institut GIMI, CHU Dijon Bourgogne, Dijon, France
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Affiliation as printed
Department of Clinical Genetics, Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark
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Affiliation as printed
Pediatrics and Adolescent Medicine, Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark
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Affiliation as printed
(')s Heeren Loo Zorggroep, Advisium, Ermelo, The Netherlands
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St George's Hospital · St George's, University of London · St George’s University Hospitals NHS Foundation Trust
Affiliation as printed
St George's University Hospitals NHS Foundation Trust & St Georges, University of London, IMBE, London, United Kingdom; Department of Molecular and Biomedical Sciences, City St, University of London, London, United Kingdom
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UNSW Sydney · Sydney Children’s Hospitals Network
Affiliation as printed
Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; Centre for Clinical Genetics, Sydney Children's Hospitals Network, Randwick, NSW, Australia
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Affiliation as printed
Department of Human Genetics, Hadassah University Hospital, Jerusalem, Israel
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St Mary's Hospital · Manchester University NHS Foundation Trust
Affiliation as printed
Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Oxford Road, Manchester, United Kingdom
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Tel Aviv Sourasky Medical Center
Affiliation as printed
Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
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Guy's and St Thomas' NHS Foundation Trust · St Mary's Hospital · Manchester University NHS Foundation Trust
Affiliation as printed
Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Oxford Road, Manchester, United Kingdom; Department of Clinical Genetics, Guy's & St Thomas NHS Foundation Trust, London, United Kingdom
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Birmingham Women's Hospital · Birmingham Women’s and Children’s NHS Foundation Trust
Affiliation as printed
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, United Kingdom
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Great Ormond Street Hospital · Great Ormond Street Hospital for Children NHS Foundation Trust
Affiliation as printed
Clinical Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
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Cristina Dias corresponding
King's College London · Guy's and St Thomas' NHS Foundation Trust · Great Ormond Street Hospital for Children NHS Foundation Trust · The Francis Crick Institute
Affiliation as printed
Clinical Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; Neural Stem Cell Biology Lab, The Francis Crick Institute, London, United Kingdom; Department of Medical and Molecular Genetics, School of Basic & Medical Biosciences, King's College London, London, United Kingdom; Department of Clinical Genetics, Guy's & St Thomas NHS Foundation Trust, London, United Kingdom. Electronic address: cristina.dias@kcl.ac.uk
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