Article Text
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.
- genetic variation
- congenital
- hereditary
- gene expression regulation
- neonatal diseases
- abnormalities
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. De-identified individual participant data and in vitro study materials, such as SOX4 variant expression plasmids, will be made available on request to the corresponding authors, subject to the participant data sharing plan and consent provided.
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Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. De-identified individual participant data and in vitro study materials, such as SOX4 variant expression plasmids, will be made available on request to the corresponding authors, subject to the participant data sharing plan and consent provided.
Footnotes
CG, RCA-N and VL are joint senior authors.
Contributors MA, CG, RCA-N and VL designed this study. MA, DT and AK performed most of the in silico and in vitro functional tests. MA, AK, ANM, ALR, JL, CG, RCA-N and VL analysed the data and wrote the manuscript. All other authors helped recruit patients and provided clinical information. All authors read, provided feedback and approved the manuscript. RCA-N and VL are guarantors of the overall content of the paper.
Funding This work was funded by the Children’s Hospital of Philadelphia (VL and RAN), National Institute of Health NIAMS R01-AR68308 grant (VL), National Institute of Health NINDS K08-NS105865 grant (RAN) and National Institute of Health NIMH R01MH074090 and U01MH119705 grants (SMM). MB and LF are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA). Genome sequencing was funded for one patient by an internal grant from Children’s of Alabama and the HudsonAlpha Institute for Biotechnology Clinical Services Laboratory (ACEH, MD, KS). The inclusion of one patient was made possible through access to the France Genomic Medicine Plan 2025 database.
Competing interests AC and MJT are employees of GeneDx, Inc. Other authors have no competing interests.
Provenance and peer review Not commissioned; externally peer reviewed.
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