Domain‐Specific Genotype–Phenotype Correlations in DNM1L Disorders: Insights Into Mutation Hotspots and Clinical Severity

ABSTRACT

DNM1L‐related disorders are rare mitochondrial diseases characterized by defective fission dynamics, often presenting with severe neurological manifestations. Current diagnostic and prognostic challenges stem from incomplete knowledge of domain‐specific genotype–phenotype correlations and limited clinical data. We report a novel GTPase effector domain (GED) variant (p.Val687del) and conduct a systematic analysis of 80 reported DNM1L cases with variants in the GTPase, Middle, or GED domains. Clinical, genetic, and survival data were extracted and analyzed to evaluate associations between mutation localization and clinical outcomes. Statistical comparisons of phenotypic severity, survival, and hotspot prevalence were performed. Functional validation of the novel variant was performed through in vitro overexpression, Western blot, immunofluorescence, and transmission electron microscopy. A novel GED deletion (p.Val687del) associated with peripheral neuropathy was identified, expanding the mutational spectrum. In vitro functional studies confirmed that this variant impairs DRP1 mitochondrial localization and induces severe ultrastructural damage, including fragmentation, swelling, and vacuolation. The preserved protein expression level excludes haploinsufficiency, consistent with a dominant‐negative mechanism. Within the total cohort of 81 patients (including our case), de novo variants were predominant (74.1%), with R403C representing a major mutational hotspot (28.4%). Middle domain mutations conferred the most severe prognosis, manifesting high frequencies of developmental delay (90.7%), epilepsy (83.7%), abnormal muscle tone (67.4%), abnormal EEG findings (74.4%), and cerebral atrophy (73.2%). In contrast, GTPase domain mutations primarily affected sensory pathways, with optic atrophy (57.6%) and peripheral neuropathy (27.3%) as hallmark features. Carriers of the R403C variant exhibited a 3.9‐year delay in disease onset compared to non‐carriers. This study establishes that mutation location in DNM1L dictates clinical severity, with Middle domain variants defining a severe encephalopathic subtype, while GTPase domain mutations predominantly target sensory pathways, leading to optic atrophy and peripheral neuropathy. These findings provide a framework for precision prognostication and targeted therapeutic strategies in DNM1L‐related disorders.