Refining Domain-Based Prognostication in DNM1 Encephalopathy: A Mild Phenotype Associated With a GTPase Domain...

DNM1 encephalopathy is a rare autosomal dominant genetic condition characterized by a range of neurological and developmental manifestations. The typical phenotype is severe, including profound intellectual disability, treatment-resistant epilepsy, ataxia, and structural brain abnormalities. However, milder presentations have increasingly been reported, suggesting that the full phenotypic spectrum remains incompletely defined. We describe the case of a female patient who presents only with well-controlled epilepsy and mild dysmorphic features. Trio exome sequencing identified a de novo likely pathogenic variant in the GTPase domain of DNM1, supporting the diagnosis of DNM1 encephalopathy. Historically, disease-causing variants in the GTPase domain were thought to confer a more severe presentation. However, our patient demonstrates a more attenuated phenotype than previously reported cases, including those viewed as mild, which have consistently included some degree of developmental impairment. This supports an expanded and more variable phenotypic spectrum of DNM1 encephalopathy than previously recognized. This additionally complicates domain-based prognostication; though further cases will aid in elucidating genotype-phenotype correlation.