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. 2022 Feb;30(2):243-247.
doi: 10.1038/s41431-021-00968-w. Epub 2021 Nov 8.

Biallelic in-frame deletion of SOX4 is associated with developmental delay, hypotonia and intellectual disability

Affiliations

Biallelic in-frame deletion of SOX4 is associated with developmental delay, hypotonia and intellectual disability

Amama Ghaffar et al. Eur J Hum Genet. 2022 Feb.

Abstract

Intellectual disability (ID) represents an extremely heterogeneous group of disorders, characterized by significant limitations in intellectual function and adaptive behavior. Among the monogenic causes, autosomal recessive genes (ARID) are responsible for more than 50% of ID. Here, we report a novel in-frame homozygous deletion variant [c.730_753del; p.(Ala244_Gly251del)] in SOX4 (sex-determining region Y-related high-mobility group box 4), segregating with moderate to severe ID, hypotonia, and developmental delay in a Pakistani family. Our identified variant p.(Ala244_Gly251del) is predicted to remove evolutionarily conserved residues from the interdomain region and may destabilize the protein secondary structure. SOX4 belongs to group C of the SOX transcription regulating family known to be involved in early embryo development. Single-cell RNA data analysis of developing telencephalon revealed highly overlapping expression of SOX4 with SOX11 and DCX, known neurogenesis regulators. Our study expands the mutational landscape of SOX4 and the repertoire of the known genetic causes of ARID.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Phenotype and genetic analysis of SOX4 variant.
A Pedigree of family PKMR225. The filled symbols represent affected individuals, and a double horizontal line connecting parents represents a consanguineous marriage. Genotypes for the identified SOX4 variant are given for the participating individuals. B Photographs and T2-weighted MRI images of affected individuals (IV:1 and IV:2). Facial feature recognition analysis revealed mild facial dysmorphism in both individuals. Affected individual IV:1 has a long triangular face with deep-set eyes, micrognathia, and high palate, while affected individual IV:2 has an upslanted palpebral fissure, broad base nose, and diastema. Both affected individuals have normal hands and no brain tissue abnormality was noted in the MRI scans. C SOX4 has a single coding exon gene. Shown are all four reported de novo (black) variants and the novel variant c.730_753del (red) found in this study. D Evolutionary conservation of amino acids deleted due to the c.730_753del variant [Color code Red: Small (small + hydrophobic [includes aromatic –Y]), Blue: Acidic, Green: Hydroxyl + sulfhydryl + amine + G]. E Tolerance landscape visualization of SOX4 via MetaDome with relative positions of the four reported de novo missense and novel in-frame deletion variants. The graph indicates that variants within the HMG domain are “highly intolerant,” while the in-frame deletion outside the HMG domain is also “intolerant” for substitutions.
Fig. 2
Fig. 2. 3D modeling and single-cell RNA expression analysis of SOX4, and downstream known target genes in developing human brain tissues.
A 3D SOX4 protein modeling. Hydrogen bonding between the residues is shown with dotted lines along with the distances in Å. At least seven predicted hydrogen bonds are lost due to the p. Ala244_Glu251 variant. B Single-cell RNA-seq visualization of SOX4 RNA expression with its interactors DCX, Sox11, TBR2, and WDR45 using UCSC cell browser for cortex development dataset, generated from expression of 4261 cells. Gene panels show expression data plotted in t-SNE on WGCNA layout, areas of interest are highlighted with orange lines, beige to dark brown show high RNA expression levels whereas blue shows absence of expression in developing human telencephalon. For cell type clustering details, see https://cells.ucsc.edu/?ds=cortex-dev. MGE medial ganglionic eminence, IPC intermediate progenitor cells.

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