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.
Frontiers in Pediatrics
|October 30, 2023
Summary
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.
