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Identification of a DLG3 stop mutation in the MRX20 family

European Journal of Human Genetics volume 32, pages 317–323 (2024)Cite this article

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Abstract

Here, we identified the causal mutation in the MRX20 family, one of the larger X-linked pedigrees that have been described in which no gene had been identified up till now. In 1995, the putative disease gene had been mapped to the pericentromeric region on the X chromosome, but no follow-up studies were performed. Here, whole exome sequencing (WES) on two affected and one unaffected family member revealed the c.195del/p.(Thr66ProfsTer55) mutation in the DLG3 gene (NM_021120.4) that segregated with the affected individuals in the family. DLG3 mutations have been consequently associated with intellectual disability and are a plausible explanation for the clinical abnormalities observed in this family. In addition, we identified two other variants co-segregating with the phenotype: a stop gain mutation in SSX1 (c.358G>T/p.(Glu120Ter)) (NM_001278691.2) and a nonsynonymous SNV in USP27X (c.56 A>G/p.(Gln19Arg)) (NM_001145073.3). RNA sequencing revealed 14 differentially expressed genes (p value < 0.1) in 7 affected males compared to 4 unaffected males of the family, including four genes known to be associated with neurological disorders. Thus, in this paper we identified the c.195del/p.(Thr66ProfsTer55) mutation in the DLG3 gene (NM_021120.4) as likely responsible for the phenotype observed in the MRX20 family.

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Fig. 1: Pedigree of the MRX20 family.
Fig. 2: DNA sequencing chromatogram of the variants found in DLG3, SSX1, and USP27X in the MRX20 family.
Fig. 3: Differential expression and enriched pathway analysis.
Fig. 4: Representation of the synapse-associate protein 102 (SAP102) encoded by the Discs Large MAGUK Scaffold Protein 3 (DLG3) gene.

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Data availability

The datasets generated during the current study are not publicly available due consent restrictions, but are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Cheryl S. Reid for family consultation.

Funding

The authors acknowledge the support of the Research Fund of the University of Antwerp OEC-Methusalem grant “GENOMED”.

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Authors and Affiliations

  1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

    Jolien Huyghebaert, Ligia Mateiu, Ellen Elinck, Kirsten Esther Van Rossem, Bregje Christiaenssen, Claudio Peter D’Incal, Geert Vandeweyer & R. Frank Kooy

  2. Department of Psychiatry, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA

    Michael K. McCormack

  3. Department of Cell Biology and Neurosciences, Virtua Health College of Medicine and Life Sciences of Rowan University, Stratford, NJ, 08084, USA

    Michael K. McCormack

  4. Department of Neurology, Rutgers University-Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA

    Alice Lazzarini

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Contributions

Clinical examination and counseling of the family were performed by AL and MKM. JH was responsible for the conceptualization and overview of the experiments under the supervision of RFK and GV. Primers were developed by JH and EE. Experiments were executed by JH, EE, KEVR, and BC. GV analyzed the WES data. Differential expression was analyzed by LM. Pathway enrichment analysis and identification of enriched transcription factors were performed by JH and LM. Analysis of RT-PCR data and preparation of the corresponding figures were performed by JH and CPD. Western Blotting was performed by CPD. JH drafted the manuscript, which was reviewed and approved by all authors.

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Correspondence to R. Frank Kooy.

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The cell lines used in this study were donated with informed consent to the Human Genetic Mutant Cell Repository at the Coriell Institute (Camden, New Jersey, USA) for research purposes.

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Huyghebaert, J., Mateiu, L., Elinck, E. et al. Identification of a DLG3 stop mutation in the MRX20 family. Eur J Hum Genet 32, 317–323 (2024). https://doi.org/10.1038/s41431-024-01537-7

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