Further delineation of the SCAF4-associated neurodevelopmental disorder

Schmid CM, Gregor A, Ruiz A, Manso Bazús C, Herman I, Ammouri F, Kotzaeridou U, McNiven V, Dupuis L, Steindl K, Begemann A, Rauch A, Suter AA, Isidor B, Mercier S, Nizon M, Cogné B, Deb W, Besnard T, Haack TB, Falb RJ, Müller AJ, Linden T, Haldeman-Englert CR, Ockeloen CW, Mattioli F, Reymond A, Ibrahim N, Naz S, Lacaze E, Bassetti JA, Hoefele J, Brunet T, Riedhammer KM, Elloumi HZ, Person R, Zou F, Kahle JJ, Cremer K, Schmidt A, Delrue MA, Almeida PM, Ramos F, Srivastava S, Quinlan A, Robertson S, Manka E, Kuechler A, Spranger S, Nowaczyk MJ, Elshafie RM, Alsharhan H, Hillman PR, Dunnington LA, Braakman HM, McKee S, Moresco A, Ignat AD, Newbury-Ecob R, Banneau G, Patat O, Kuerbitz J, Rzucidlo S, Sell SS, Gordon P, Schuhmann S, Reis A, Halleb Y, Stoeva R, Keren B, Al Masseri Z, Tümer Z, Hammer-Hansen S, Krüger Sølyst S, Steigerwald CG, Abreu NJ, Faust H, Müller-Nedebock A, Tran Mau-Them F, Sticht H, Zweier C (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Article Number: 103

DOI: 10.1038/s41431-024-01760-2

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.

Authors with CRIS profile

Involved external institutions

Hamilton Health Sciences (HHS) Canada (CA) The Hospital for Sick Children (SickKids) Canada (CA) University of Zurich / Universität Zürich (UZH) Switzerland (CH) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) France (FR) Centre Hospitalier Universitaire (CHU) de Toulouse France (FR) Baylor College of Medicine United States (USA) (US) Rigshospitalet Denmark (DK) Carl von Ossietzky Universität Oldenburg Germany (DE) Ministry of Health Kuwait (KW) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Université de Lausanne (UNIL) Switzerland (CH) Lahore College for Women University (LCWU) / لاہور کالج برائے خواتین یونیورسٹی Pakistan (PK) Groupe Hospitalier du Havre France (FR) Belfast Health and Social Care Trust United Kingdom (GB) Penn State Health Children's Hospital United States (USA) (US) Centre Hospitalier Le Mans France (FR) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Al Qatif Central Hospital Saudi Arabia (SA) Western University Canada (CA) Klinikum rechts der Isar Germany (DE) University Hospitals Bristol NHS Foundation Trust United Kingdom (GB) GeneDX United States (USA) (US) New York University (NYU) United States (USA) (US) Universitätsklinikum Bonn Germany (DE) Université de Montréal Canada (CA) Centro Hospitalar e Universitário de Coimbra (CHUC) Portugal (PT) Inselspital, Universitätsspital Bern Switzerland (CH) Institute of Research and Innovation Parc Tauli (IRIPT) / Institut d'Investigació i Innovació Parc Taulí (I3PT) Spain (ES) Klinikverbund Bremen (Gesundheit Nord) Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) McMaster University Canada (CA) Weill Cornell Medicine United States (USA) (US) Boston Children's Hospital United States (USA) (US) University of Otago New Zealand (NZ) Universitätsklinikum Essen Germany (DE) Universität Leipzig Germany (DE) Centre hospitalier universitaire (CHU) de Dijon Bourgogne France (FR) The University of Kansas Health System (UKHS) United States (USA) (US) Universitätsklinikum Heidelberg Germany (DE)

How to cite

APA:

Schmid, C.M., Gregor, A., Ruiz, A., Manso Bazús, C., Herman, I., Ammouri, F.,... Zweier, C. (2024). Further delineation of the SCAF4-associated neurodevelopmental disorder. European Journal of Human Genetics. https://doi.org/10.1038/s41431-024-01760-2

MLA:

Schmid, Cosima M., et al. "Further delineation of the SCAF4-associated neurodevelopmental disorder." European Journal of Human Genetics (2024).

BibTeX: Download