Abstract

Purpose DNM1-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.

Methods Phenotypic data was manually curated from 95 individuals from multiple sources and harmonized using the Human Phenotype Ontology framework.

Results Disease-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.

Conclusion A 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.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was funded by the NIH National Institute for Neurological Disorders and Stroke (R01 NS127830 and R01 NS131512 to IH and K23 NS140491 to JLM) and the Career Ladder Education Program for Genetic Counselors grant from the Warren Alpert Foundation (SMR). KO is supported by Estonian Research Council grant PRG2040.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was reviewed by the Childrens Hospital of Philadelphia Institutional Review Board (IRB) as part of the Epilepsy Genetics Research Project (EGRP) 15-12226. All institutions involved in participant recruitment received local IRB approval. Informed consent was obtained from all participants. Data provided to the Childrens Hospital of Philadelphia from collaborators was de-identified.

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AbbreviationsACMGAmerican College of Medical Genetics and GenomicsASManti-seizure medicationsCHOPChildren’s Hospital of PhiladelphiaDEEdevelopmental and epileptic encephalopathyEOEEearly onset epileptic encephalopathyHPOHuman Phenotype OntologyNDDneurodevelopmental disorders