De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism

Abstract

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

“…Also, SOX3 missense variant was detected in proband with mild intellectual disability ( Jelsig et al, 2018 ). Furthermore, it was found that SOX4 heterozygous missense variants cause neurodevelopmental disease ( Zawerton et al, 2019 ). On the other side, SOX5 haploinsufficiency and its loss of function variant have been found in probands with intellectual disability ( Lamb et al, 2012 ; Schanze et al, 2013 ; Nesbitt et al, 2015 ).…”

Sorting Sox: Diverse Roles for Sox Transcription Factors During Neural Crest and Craniofacial Development

“…Additionally, there have been four cases of CSS where heterozygous mutations in SOX4 have been identified. Like SOX11, these mutations were within the HMG domain and variant proteins were unable to bind DNA and activate target gene expression (Zawerton et al, 2019). Little is known about the roles of SoxC factors in the context of craniofacial development.…”

Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome

“…Genes in the BAF (Brahma/BRG1-associated factor) complex are essential in chromatin remodeling. Pathogenic variants in this complex have been associated with a number of conditions, including Coffin-Siris syndrome (CSS, MIM 135900, ORPHA:1465), Nicolaides-Baraitser syndrome (NCBRS, MIM 601358) and other CSS-like conditions ( SOX4 ) [ 1 , 2 ]. A range of learning and developmental differences, organ-related anomalies, and variable physical and facial features typically characterize BAFopathies, a term that has been proposed in its description.…”