Further delineation of the SCAF4-associated neurodevelopmental disorder.

Autor: Schmid CM; Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland.; Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland., Gregor A; Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland.; Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland., Ruiz A; Center for Genomic Medicine, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain., Manso Bazús C; Center for Genomic Medicine, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain., Herman I; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Department of Neurosciences, Boystown National Research Hospital, Boystown, TX, USA.; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Ammouri F; The University of Kansas Health System, Westwood, KS, USA., Kotzaeridou U; Division of Child Neurology and Inherited Metabolic Diseases, Centre for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., McNiven V; Division of Genetics, Department of Pediatrics, McMaster Children's Hospital, Hamilton, ON, Canada., Dupuis L; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada., Steindl K; Institute of Medical Genetics, University of Zurich, Zurich, Switzerland., Begemann A; Institute of Medical Genetics, University of Zurich, Zurich, Switzerland., Rauch A; Institute of Medical Genetics, University of Zurich, Zurich, Switzerland., Suter AA; Institute of Medical Genetics, University of Zurich, Zurich, Switzerland., Isidor B; Department of Medical Genetics, CHU Nantes, Nantes, France., Mercier S; Department of Medical Genetics, CHU Nantes, Nantes, France., Nizon M; Department of Medical Genetics, CHU Nantes, Nantes, France., Cogné B; Department of Medical Genetics, CHU Nantes, Nantes, France., Deb W; Department of Medical Genetics, CHU Nantes, Nantes, France., Besnard T; Department of Medical Genetics, CHU Nantes, Nantes, France., Haack TB; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.; Center for Rare Diseases, University of Tübingen, Tübingen, Germany., Falb RJ; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Müller AJ; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Linden T; University Children's Hospital, Klinikum Oldenburg, Department of Neuropediatrics, Oldenburg, Germany., Haldeman-Englert CR; Mission Fullerton Genetics Center, Asheville, NC, USA., Ockeloen CW; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands., Mattioli F; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland., Reymond A; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland., Ibrahim N; Lahore College for Women University, Lahore, Pakistan., Naz S; Lahore College for Women University, Lahore, Pakistan., Lacaze E; Department of Medical Genetics, Le Havre Hospital, Le Havre, France., Bassetti JA; Division of Medical Genetics, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA., Hoefele J; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany., Brunet T; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany., Riedhammer KM; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany., Elloumi HZ; GeneDx, Gaithersburg, MD, USA., Person R; GeneDx, Gaithersburg, MD, USA., Zou F; GeneDx, Gaithersburg, MD, USA., Kahle JJ; GeneDx, Gaithersburg, MD, USA., Cremer K; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Schmidt A; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Delrue MA; Department of Genetics, Université de Montréal, Sainte-Justine University Hospital, Montreal, Canada., Almeida PM; Medical Genetics Unit, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal., Ramos F; Medical Genetics Unit, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal.; Centro de Diagnóstico Pré-natal, Unidade Local de Saúde de Coimbra, Coimbra, Portugal., Srivastava S; Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Quinlan A; Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Robertson S; Department of Pediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand., Manka E; Center for Rare Disease Essen (Essener Zentrum für Seltene Erkrankungen-EZSE), Universitätsmedizin Essen, Essen, Germany., Kuechler A; Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany., Spranger S; Praxis für Humangenetik, Klinikum Bremen-Mitte, Bremen, Germany., Nowaczyk MJM; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada., Elshafie RM; Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat, Kuwait., Alsharhan H; Kuwait Medical Genetics Centre, Ministry of Health, Sulaibikhat, Kuwait.; Department of Pediatrics, Health science center, College of Medicine, Kuwait University, P.O. Box 24923, Safat, Kuwait., Hillman PR; Department of Pediatrics, Division of Medical Genetics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children's Memorial Hermann Hospital, Houston, TX, USA., Dunnington LA; Department of Pediatrics, Division of Medical Genetics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children's Memorial Hermann Hospital, Houston, TX, USA., Braakman HMH; Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center & Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands., McKee S; Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern, Ireland., Moresco A; Division of Clinical Genetics, Pediatric Department, Children's Hospital, London Health Sciences Centre, Western University, London, ON, Canada., Ignat AD; Division of Clinical Genetics, Pediatric Department, Children's Hospital, London Health Sciences Centre, Western University, London, ON, Canada., Newbury-Ecob R; Clinical Genetics, University Hospitals Bristol, Southwell St, Bristol, UK., Banneau G; Department of Medical Genetics, Toulouse University Hospital, Toulouse, France., Patat O; Department of Medical Genetics, Toulouse University Hospital, Toulouse, France., Kuerbitz J; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.; Cain Pediatric Neurology Research Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Rzucidlo S; Penn State Health Children's Hospital, Department of Pediatrics, Division of Human Genetics, Hershey, PA, USA., Sell SS; Penn State Health Children's Hospital, Department of Pediatrics, Division of Human Genetics, Hershey, PA, USA., Gordon P; Penn State Health Children's Hospital, Department of Pediatrics, Division of Human Genetics, Hershey, PA, USA., Schuhmann S; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Reis A; Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.; Centre for Rare Diseases Erlangen (ZSEER), Erlangen, Germany., Halleb Y; Le Mans Hospital, Department of Medical Genetics, Le Mans, France., Stoeva R; Le Mans Hospital, Department of Medical Genetics, Le Mans, France., Keren B; Department of Genetics, Assistance Publique - Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France., Al Masseri Z; Department of Pediatrics, Medical Genetics Unit, Qatif Central Hospital, Eastern Health Cluster, Dammam, Saudi Arabia., Tümer Z; Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Hammer-Hansen S; Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Krüger Sølyst S; Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Steigerwald CG; Division of Neurogenetics, Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA., Abreu NJ; Division of Neurogenetics, Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA., Faust H; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Müller-Nedebock A; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Tran Mau-Them F; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, CHU Dijon Bourgogne, Dijon, France.; Génétique des Anomalies Du Développement, INSERM 123, Université de Bourgogne, Dijon, France., Sticht H; Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Zweier C; Department of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland. christiane.zweier@insel.ch.; Department for Biomedical Research (DBMR), University of Bern, Bern, Switzerland. christiane.zweier@insel.ch.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Dec 12. Date of Electronic Publication: 2024 Dec 12.
DOI: 10.1038/s41431-024-01760-2
Abstrakt: While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder. The molecular spectrum comprises 25 truncating, eight splice-site and five missense variants. While all other truncating variants were classified as pathogenic/likely pathogenic, significance of one C-terminal truncating variant, one splice-site variant and the missense variants remained unclear. Three missense variants in the CTD-interacting domain of SCAF4 were predicted to destabilize the domain. Twenty-three variants occurred de novo, and variants were inherited in 13 cases. Frequent clinical findings were mild developmental delay with speech impairment, seizures, and skeletal abnormalities such as clubfoot, scoliosis or hip dysplasia. Cognitive abilities ranged from normal IQ to severe intellectual disability (ID), with borderline to mild ID in the majority of individuals. Our study confirms the role of SCAF4 variants in neurodevelopmental disorders and further delineates the associated clinical phenotype.
Competing Interests: Competing interests: HZE, RP, FZ and JK are employees of GeneDx, LLC. The remaining authors declare no conflicts of interest. Ethics: The research protocol fulfilled the requirements of the local institutional ethics committee (Kantonale Ethikkommission Bern, 2021-01396). Consent for publication of genetic and clinical data, as well as photographs was obtained from the individuals, their parents, or legal guardians, respectively. The study complied with the principles set out in the Declaration of Helsinki.
(© 2024. The Author(s).)
Databáze: MEDLINE
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