A neurodevelopmental syndrome was recently reported in four patients with 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. We newly identified 17 patients with variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. 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 related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to haploinsufficiency in neurogenesis and multiple other developmental processes.