Veröffentlicht: 12. Dezember 2024 ; Gesehen am 24.06.2025
Autism spectrum disorders; Genetics research
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 genetics Basingstoke : Stockton Press, 1998 33(2025), 5, Seite 588-594 Online-Ressource
von Kim M. Thalwitzer ; Jan Henje Driedger ; Julie Xian ; Afshin Saffari ; Pia Zacher ; Bigna K. Bölsterli ; Sarah McKeown Ruggiero ; Katie Rose Sullivan ; Alexandre N. Datta ; Christoph Kellinghaus ; Jürgen Althaus ; Adelheid Wiemer-Kruel ; Andreas van Baalen ; Armin Pampel ; Michael Alber ; Hilde M. H. Braakman ; Otfried Martin Debus ; Jonas Denecke ; Elke Hobbiebrunken ; Ina Breitweg ; Danielle Diehl ; Hans Christian Eitel ; Janina Gburek-Augustat ; Martin Preisel ; Jan-Ulrich Schlump ; Mirjam Laufs ; Dilbar Mammadova ; Carsten Wurst ; Christine Prager ; Christa Löhr-Nilles ; Peter Martin ; Sven Garbade ; Konrad Platzer ; Ira Benkel-Herrenbrueck ; Kerstin Egler ; Walid Fazeli ; Johannes R. Lemke ; Eva Runkel ; Barbara Klein ; Tobias Linden ; Julian Schröter ; Heike Steffeck ; Bastian Thies ; Florian von Deimling ; Sabine Illsinger ; Ingo Borggräfe ; Georg Classen ; Dagmar Wieczorek ; Georgia Ramantani ; Stefan Kölker ; Georg F. Hoffmann ; Markus Ries ; Ingo Helbig ; Steffen Syrbe
BACKGROUND AND OBJECTIVES: Pathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control. - METHODS: We performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1-related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System scores (GMFCS) and a speech impairment score and were compared within and across clinically defined subgroups. - RESULTS: We collected data of 71 individuals with STXBP1-related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (IQR = 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including two individuals presenting with close to age-appropriate motor development. 29/61 (48%) individuals were able to walk unassisted and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs. 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs. 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores (p = 0.02) than individuals with later epilepsy onset. - DISCUSSION: We expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with epilepsy, in particular epileptic spasms, and neonatal or early-onset, presented with less favorable motor and language functional outcomes compared to individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1-related disorders.
von Matthias Lange ; Tobias Linden ; Hermann L. Müller ; Meera A. Flasskuehler ; Holger Köster ; Kai Lehmberg ; Svea Ledig ; Stephan Ehl ; Axel Heep ; Florian Beske
von Bettina Mucha ; Siddarth Banka ; Norbert Fonya Ajeawung ; Sirinart Molidperee ; Gary G. Chen ; Mary Kay Koenig ; Rhamat B. Adejumo ; Marianne Till ; Michael Harbord ; Renee Perrier ; Emmanuelle Lemyre ; Renee-Myriam Boucher ; Brian G. Skotko ; Jessica L. Waxler ; Mary Ann Thomas ; Jenelle C. Hodge ; Jozef Gecz ; Jillian Nicholl ; Lesley McGregor ; Tobias Linden
von Bettina Mucha ; Siddarth Banka ; Norbert Fonya Ajeawung ; Sirinart Molidperee ; Gary G. Chen ; Mary Kay Koenig ; Rhamat B. Adejumo ; Marianne Till ; Michael Harbord ; Renee Perrier ; Emmanuelle Lemyre ; Renee-Myriam Boucher ; Brian G. Skotko ; Jessica L. Waxler ; Mary Ann Thomas ; Jenelle C. Hodge ; Jozef Gecz ; Jillian Nicholl ; Lesley McGregor ; Tobias Linden
