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

European Journal of Human Genetics volume 30, pages 243–247 (2022)Cite this article

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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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Fig. 1: Phenotype and genetic analysis of SOX4 variant.
Fig. 2: 3D modeling and single-cell RNA expression analysis of SOX4, and downstream known target genes in developing human brain tissues.

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Data availability

The variant has been submitted to ClinVar database (accession number: SCV001571323).

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Acknowledgements

We thank the PKMR225 family members for participating in this study. We would like to thank Muhammad Asad Usmani for his guidance and technical assistance.

Funding

This work was supported by National Institute of Neurological Disorders and Stroke, National Institutes of Health grant R01NS107428 to Saima Riazuddin.

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Authors and Affiliations

  1. Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA

    Amama Ghaffar, Zubair M. Ahmed & Saima Riazuddin

  2. National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan

    Amama Ghaffar, Faiza Rasheed & Muhammad Rashid

  3. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HE, Nijmegen, The Netherlands

    Hans van Bokhoven

  4. Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA

    Zubair M. Ahmed & Saima Riazuddin

  5. Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan

    Sheikh Riazuddin

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  1. Amama Ghaffar
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  2. Faiza Rasheed
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Correspondence to Saima Riazuddin.

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The authors declare no competing interests.

Ethics approval

This study was approved by the Institutional Review Boards (IRB) at the University of Maryland Baltimore, USA, and the Centre of Excellence in Molecular Biology (CEMB), University of The Punjab, Lahore, Pakistan.

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Ghaffar, A., Rasheed, F., Rashid, M. et al. Biallelic in-frame deletion of SOX4 is associated with developmental delay, hypotonia and intellectual disability. Eur J Hum Genet 30, 243–247 (2022). https://doi.org/10.1038/s41431-021-00968-w

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