Domain-Specific Genotype-Phenotype Correlations in DNM1L Disorders: Insights Into Mutation Hotspots and Clinical...

Area of Science:

• Genetics
• Mitochondrial Biology
• Neurology

Background:

• DNM1L-related disorders are rare mitochondrial diseases with severe neurological symptoms.
• Current diagnostics and prognostics are challenged by limited genotype-phenotype data.
• DNM1L protein regulates mitochondrial dynamics through fission.

Purpose of the Study:

• To investigate genotype-phenotype correlations in DNM1L disorders.
• To analyze the impact of mutation location within DNM1L domains on clinical outcomes.
• To characterize a novel DNM1L variant (p.Val687del) and its functional consequences.

Main Methods:

• Systematic analysis of 80 reported DNM1L cases and one novel case.
• Extraction and statistical analysis of clinical, genetic, and survival data.
• In vitro functional studies (overexpression, Western blot, immunofluorescence, electron microscopy) of the novel variant.

Main Results:

• A novel GTPase Effector Domain (GED) deletion (p.Val687del) was identified, causing peripheral neuropathy.
• Middle domain mutations are associated with severe encephalopathy (developmental delay, epilepsy, cerebral atrophy).
• GTPase domain mutations primarily impact sensory pathways (optic atrophy, peripheral neuropathy).

Conclusions:

• Mutation location within DNM1L domains is a key determinant of clinical severity and phenotype.
• Middle domain variants define a severe encephalopathic subtype.
• GTPase domain variants predominantly affect sensory pathways, offering a framework for prognostication and targeted therapies.