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

Marco Angelozzi, Anirudha Karvande, Arnaud N. Molin, Alyssa L. Ritter, Jacqueline M.M. Leonard, Juliann M. Savatt, Kristen Douglass, Scott M. Myers, Mina Grippa, Dara Tolchin, Elaine Zackai, Sarah Donoghue, Anna C.E. Hurst, Maria Descartes, Kirstin Smith, Danita Velasco, Andrew Schmanski, Amy Crunk, Mari J. Tokita, Iris M. De LangeKoen Van Gassen, Hannah Robinson, Katie Guegan, Mohnish Suri, Chirag Patel, Marie Bournez, Laurence Faivre, Frédéric Tran-Mau-Them, Janice Baker, Noelle Fabie, K. Weaver, Amelle Shillington, Robert J. Hopkin, Daniela Q.C.M. Barge-Schaapveld, Claudia A.L. Ruivenkamp, Regina Bökenkamp, Samantha Vergano, Maria Noelia Seco Moro, Aranzazu Díaz De Bustamante, Vinod K. Misra, Kelly Kennelly, Caleb Rogers, Jennifer Friedman, Kristen M. Wigby, Jerica Lenberg, Claudio Graziano, Rebecca C. Ahrens-Nicklas, Veronique Lefebvre

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1058-1068
Number of pages11
JournalJournal of medical genetics
Issue number11
StatePublished - Mar 1 2022


  • abnormalities
  • congenital
  • gene expression regulation
  • genetic variation
  • hereditary
  • neonatal diseases

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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