Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome. Issue 11 (1st March 2022)

• Record Type: Journal Article
• Authors: Angelozzi, Marco; Karvande, Anirudha; Molin, Arnaud N; Ritter, Alyssa L; Leonard, Jacqueline M M; Savatt, Juliann M; Douglass, Kristen; Myers, Scott M; Grippa, Mina; Tolchin, Dara; Zackai, Elaine; Donoghue, Sarah; Hurst, Anna C E; Descartes, Maria; Smith, Kirstin; Velasco, Danita; Schmanski, Andrew; Crunk, Amy; Tokita, Mari J; de Lange, Iris M; van Gassen, Koen; Robinson, Hannah; Guegan, Katie; Suri, Mohnish; Patel, Chirag; Bournez, Marie; Faivre, Laurence; Tran-Mau-Them, Frédéric; Baker, Janice; Fabie, Noelle; Weaver, K; Shillington, Amelle; Hopkin, Robert J; Barge-Schaapveld, Daniela Q C.M; Ruivenkamp, Claudia AL; Bökenkamp, Regina; Vergano, Samantha; Seco Moro, Maria Noelia; Díaz de Bustamante, Aranzazu; Misra, Vinod K; Kennelly, Kelly; Rogers, Caleb; Friedman, Jennifer; Wigby, Kristen M; Lenberg, Jerica; Graziano, Claudio; Ahrens-Nicklas, Rebecca C; Lefebvre, Veronique;
• Is Part Of: Journal of medical genetics. Volume 59:Issue 11(2022)
• Page Start: 1058
• Page End: 1068
• Publication Date: 2022-03-01
• Subjects: genetic variation -- congenital -- hereditary -- gene expression regulation -- neonatal diseases -- abnormalities; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2021-108375
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. Methods: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. Results: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11- related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. Conclusion: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.