Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome

Angelozzi, M.; Karvande, A.; Molin, A.N.; Ritter, A.L.; Leonard, J.M.M.; Savatt, J.M.; Douglass, K.; Myers, S.M.; Grippa, M.; Tolchin, D.; Zackai, E.; Donoghue, S.; Hurst, A.C.E.; Descartes, M.; Smith, K.; Velasco, D.; Schmanski, A.; Crunk, A.; Tokita, M.J.; Lange, I.M. de; Gassen, K. van; Robinson, H.; Guegan, K.; Suri, M.; Patel, C.; Bournez, M.; Faivre, L.; Tran-Mau-Them, F.; Baker, J.; Fabie, N.; Weaver, K.; Shillington, A.; Hopkin, R.J.; Barge-Schaapveld, D.Q.C.M.; Ruivenkamp, C. al; Bokenkamp, R.; Vergano, S.; Moro, M.N.S.; Bustamante, A.D. de; Misra, V.K.; Kennelly, K.; Rogers, C.; Friedman, J.; Wigby, K.M.; Lenberg, J.; Graziano, C.; Ahrens-Nicklas, R.C.; Lefebvre, V.

doi:doi:10.1136/jmedgenet-2021-108375

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...Show moreBackground: 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.Show less

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Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome