Further delineation of the SCAF4-associated neurodevelopmental disorder

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.

Authors

Institutions

Publication Details

Journal
European Journal of Human Genetics
Published
2024-12-12
DOI
https://doi.org/10.1038/s41431-024-01760-2
Citations
4
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
2.20

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Further delineation of the SCAF4-associated neurodevelopmental disorder

Siddharth Srivastava, Jeffrey Kuerbitz, Sarah Schuhmann, Amelie J. Müller et al.
4 citations
European Journal of Human Genetics
Genomics and Rare Diseases
2.20
article

Further delineation of the SCAF4-associated neurodevelopmental disorder

Siddharth Srivastava, Jeffrey Kuerbitz, Sarah Schuhmann, Amelie J. Müller, Chad Haldeman‐Englert, Vanda McNiven, Marie‐Ange Delrue, Theresa Brunet, Tobias B. Haack, Christiane Zweier, Alexandre Reymond, Frédéric Tran Mau‐Them, Leslie Dunnington, Elodie Lacaze, H. Faust, Stephen P. Robertson, Zeynep Tümer, Anne Gregor, Sophia Hammer‐Hansen, Axel Schmidt, Houda Zghal Elloumi, Juliette J. Kahle, Cosima M. Schmid, Thomas Besnard, Katharina Steindl, Mathilde Nizon, Eva Manka, Anita M. Rauch, Francesca Mattioli, Tobias Linden, Charlotte W. Ockeloen, Julia Hoefele, Isabella Herman, Stephanie Spranger, Amica Corda Müller-Nedebock, Shagufta Naz, Urania Kotzaeridou, Pedro Almeida, Reem M. Elshafie, Shane McKee, Anaïs Begemann, Aisling Quinlan, Lucie Dupuis, Aude‐Annick Suter, Nazia Ibrahim, Nicolas J. Abreu, Bertrand Isidor, Angélica Moresco, Heinrich Sticht, Susan L. Sell, Paul Hillman, Radka Stoeva, Hilde M. H. Braakman, Anna Ruiz, Wallid Deb, Zainab Al Masseri, Sandra Mercier, André Reis, Ruth Falb, Hind Alsharhan, Sofus Sølyst, Connolly Steigerwald, Carmen Manso Bazús, Susan Rzucidlo, Yosra Halleb, Korbinian M. Riedhammer, Fabiana Ramos, Andrea-Diana Ignat, Farah Ammouri, Patricia Gordon, Guillaume Banneau, Ruth Newbury-Ecob, Boris Keren, Benjamin Cogné, Kirsten Cremer, Jennifer A. Bassetti, Richard Person, Alma Kuechler, Małgorzata J.M. Nowaczyk, Fanggeng Zou, Olivier Patat
article en
4 citations

Abstract

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.

European Journal of Human GeneticsVol. 33(5)
University of Bern (CH), Universitat Autònoma de Barcelona (ES), University of Copenhagen (DK), Western University (CA), Boston Children's Hospital (US), Memorial Hermann (US), Bern University of Applied Sciences (CH), Boys Town (US), University of Bonn (DE), Harvard University (US), Université Le Havre Normandie (FR), Radboud University Nijmegen (NL), University of Kansas (US), Inserm (FR), Lahore College for Women University (PK), Université de Bourgogne (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Baylor College of Medicine (US), University of Toronto (CA), University of Zurich (CH), Cornell University (US), Heidelberg University (DE), University Hospital Bonn (DE), London Health Sciences Centre (CA), University Hospital of Bern (CH), Hospital for Sick Children (CA), McMaster Children's Hospital (CA), University Hospital Heidelberg (DE), Copenhagen University Hospital (DK), TUM Klinikum (DE), Rigshospitalet (DK), Radboud University Medical Center (NL), Kuwait University (KW), Universitätsklinikum Erlangen (DE), Kennedy Center (DK), Assistance Publique – Hôpitaux de Paris (FR), Escola Superior de Tecnologia da Saúde de Coimbra (PT), Klinikum Oldenburg (DE), Corporació Sanitària Parc Taulí (ES), Qatif Central Hospital (SA), Neurological Research Institute (US), Essen University Hospital (DE), Centre Hospitalier du Mans (FR), Ministry of Health (KW), Praxis für Humangenetik (DE), Institute of Research and Innovation Parc Tauli (ES), SickKids Foundation (CA), Texas Children's Hospital (US), Comprehensive Cancer Center Erlangen (DE), Klinikum Bremen-Mitte (DE), Dammam Central Hospital (SA), Weill Cornell Medicine (US), New York University (US), University of Duisburg-Essen (DE), Technical University of Munich (DE), Université de Montréal (CA), University of Otago (NZ), University of Tübingen (DE), Penn State Milton S. Hershey Medical Center (US), The University of Texas Health Science Center at Houston (US), Leipzig University (DE), University of Lausanne (CH), McMaster University (CA)
National Science Foundation, University of Bern, European Commission, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Quality Education
Openalex Percentile: Top 11%
Genomics and Rare Diseases
2.20
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.