DNM1-related disorder is characterized by recurrent variants and phenotypic homogeneity

Abstract

PurposeDNM1-related disorder is a rare developmental and epileptic encephalopathy. The current understanding of the clinical spectrum is based on sparse patient descriptions. Here, we compile the largest DNM1 cohort to date, to characterize the genotypic and phenotypic landscape of the disorder. MethodsPhenotypic data was manually curated from 95 individuals from multiple sources and harmonized using the Human Phenotype Ontology framework. ResultsDisease-causing variants in DNM1 cluster in mutational hotspots within the gene, which achieve Strong and Moderate evidence for pathogenicity based on ACMG guidelines. The overall DNM1 phenotype was homogeneous compared to other genetic epilepsy conditions: SCN2A, SCN8A, STXBP1, and SYNGAP1. The p.R237W (n=15) variant was associated with bilateral tonic-clonic seizures, infantile spasms, and dystonia. The p.I398_R399insCR (n=14) variant was associated with severe hypotonia, profound global delay, and cortical visual impairment. Five individuals with homozygous loss-of-function variants were clinically similar to dominant-negative DNM1-related disorder, but microcephaly and brain MRI abnormalities were more common in this group. ConclusionA harmonized cohort of individuals with DNM1-related disorder was analyzed to define mutational hotspots and reveal novel genotype-phenotype correlations. Due to the homogeneous phenotype, disease mechanism, and high proportion of recurrent variants, DNM1 represents an attractive target for targeted therapy development.