Related Experiment Video
Updated: Jul 4, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Identification of a DLG3 stop mutation in the MRX20 family
Jolien Huyghebaert1, Ligia Mateiu1, Ellen Elinck1
1Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
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.
Insights
Researchers identified a DLG3 gene mutation causing intellectual disability in the large MRX20 family. This finding, using whole exome sequencing, pinpoints the genetic cause for previously unexplained neurological abnormalities in this X-linked pedigree.
Area of Science:
- Human Genetics
- Neurogenetics
- Molecular Biology
Background:
- The MRX20 family, a large X-linked pedigree with intellectual disability, lacked an identified disease gene despite previous mapping efforts.
- Understanding the genetic basis of X-linked intellectual disability is crucial for diagnosis and potential therapeutic strategies.
Purpose of the Study:
- To identify the causal genetic mutation responsible for intellectual disability in the MRX20 family.
- To investigate the role of the DLG3 gene in the observed clinical abnormalities.
Main Methods:
- Whole exome sequencing (WES) was performed on affected and unaffected family members.
- Segregation analysis was used to confirm the co-occurrence of mutations with the phenotype.
- RNA sequencing was employed to analyze gene expression differences in affected males.
Main Results:
- A pathogenic mutation (c.195del/p.(Thr66ProfsTer55)) in the DLG3 gene was identified and segregated with affected individuals.
- Two additional co-segregating variants, a SSX1 stop-gain mutation and a USP27X nonsynonymous SNV, were found.
- Differential gene expression analysis revealed 14 genes, including four neurological disorder-associated genes, were altered in affected males.
Conclusions:
- The c.195del/p.(Thr66ProfsTer55) mutation in the DLG3 gene is identified as the likely cause of the phenotype in the MRX20 family.
- DLG3 mutations are confirmed as a cause of intellectual disability, explaining the clinical presentation in this family.
- Further investigation into the identified variants and differentially expressed genes may provide deeper insights into the disease mechanism.
