Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy
Tayyaba Afsar1,2, Xiaoyun Huang3, Abid Ali Shah4
1Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
Insights
This study identifies a novel homozygous nonsense variant in the DNM1 gene causing severe neurodevelopmental disorders in a Pakistani family. The findings confirm DNM1
Area of Science:
- Genetics and Genomics
- Neuroscience
- Molecular Biology
Background:
- Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders characterized by early-onset seizures and developmental impairments.
- Variants in the DNM1 gene are linked to autosomal dominant (DEE type 31A) and recessive (DEE type 31B) forms of DEE.
Purpose of the Study:
- To identify the genetic cause of severe neurodevelopmental phenotypes in a consanguineous Pakistani family.
- To characterize a novel DNM1 gene variant and its impact on protein function and gene expression.
Main Methods:
- Whole Exome Sequencing (WES) and Sanger sequencing to identify pathogenic variants.
- Bioinformatics prediction, 3D protein modeling, molecular dynamics simulation, and RT-qPCR to assess variant pathogenicity and gene expression.
Main Results:
- A novel homozygous nonsense variant (c.1402G>T; p. Glu468*) in the DNM1 gene was identified and predicted as pathogenic.
- In silico analyses indicated the variant disrupts DNM1 protein structure and function.
- RT-qPCR demonstrated a significant reduction in DNM1 gene expression in the patient.
Conclusions:
- Homozygous, loss-of-function variants in DNM1 are confirmed to cause DEE type 31B.
- This study expands the known genotypic and phenotypic spectrum of DNM1-associated neurodevelopmental disorders.
Background:
Developmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1 gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B.
Methods:
In the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)-based mRNA expression were checked using standard methods.
Results:
Data analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene that was predicted as pathogenic class I. Variants in the DNM1 gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the DNM1 gene in the index patient.
Conclusion:
Our finding further confirms the association of homozygous, loss-of-function variants in DNM1 associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic DNM1 variants related to DNM1-associated pathogenesis.
