ArticleAmerican journal of human genetics2022
A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 29 citations in OpenAlex.
- AlphaGenome Atlas:medRxiv : the preprint server for health sciences · 2026Article
- Diagnostic Yield of Comprehensive Reanalysis After Nondiagnostic Short-Read Genome Sequencing in Infants With Unexplained Epilepsy.Neurology · 2026Article
- Beyond Clathrin: Decoding the Mechanism of Ultrafast Endocytosis.Physiology (Bethesda, Md.) · 2025Review
- Familial SYNGAP1 variants define the boundaries of a complex neurodevelopmental disorder with epilepsy.Epilepsia · 2025Article
- Progressive Cone-Rod Synaptic Dysfunction in Dynamin-1 ( DNM1 ) Related Developmental and Epileptic Encephalopathy: A Distinct Retinal Phenotype in Human.Clinical genetics · 2025Article
- Expanding the phenotypic spectrum of DNM1-related disorders: novel GTPase domain variants and their diverse neurological outcomes.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- Precision Therapeutics in Lennox-Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy.Children (Basel, Switzerland) · 2025Review
- Exploring the effects of missense mutations on protein thermodynamics through structure-based approaches: findings from the CAGI6 challenges.Human genetics · 2025Article
- Genome Sequencing of Rare Disease Patients Through the Korean Regional Rare Disease Diagnostic Support Program.Human mutation · 2025Article
- Protein isoform-centric therapeutics: expanding targets and increasing specificity.Nature reviews. Drug discovery · 2024Review
- Characterizing and predicting ccRCC-causing missense mutations in Von Hippel-Lindau disease.Human molecular genetics · 2024Article
- AI-Driven Enhancements in Drug Screening and Optimization.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Benchmarking splice variant prediction algorithms using massively parallel splicing assays.Genome biology · 2023Article
- Applications for Deep Learning in Epilepsy Genetic Research.International journal of molecular sciences · 2023Review
- Splicing defects in rare diseases: transcriptomics and machine learning strategies towards genetic diagnosis.Briefings in bioinformatics · 2023Review
- Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy.Nature communications · 2023Article
- A deep intronic variant in DNM1 in a patient with developmental and epileptic encephalopathy creates a splice acceptor site and affects only transcript variants including exon 10a.Neurogenetics · 2023Article
- Benchmarking splice variant prediction algorithms using massively parallel splicing assays.bioRxiv : the preprint server for biology · 2023Article
- Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy.Frontiers in pediatrics · 2023Article
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Authors and funding
26 authors at 15 institutions in 4 countries.
Funding
Abstract
Heterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy (DEE) as a result of a dominant-negative mechanism impeding vesicular fission. Thus far, pathogenic variants in DNM1 have been studied with a canonical transcript that includes the alternatively spliced exon 10b. However, after performing RNA sequencing in 39 pediatric brain samples, we find the primary transcript expressed in the brain includes the downstream exon 10a instead. Using this information, we evaluated genotype-phenotype correlations of variants affecting exon 10a and identified a cohort of eleven previously unreported individuals. Eight individuals harbor a recurrent de novo splice site variant, c.1197-8G>A (GenBank: NM_001288739.1), which affects exon 10a and leads to DEE consistent with the classical DNM1 phenotype. We find this splice site variant leads to disease through an unexpected dominant-negative mechanism. Functional testing reveals an in-frame upstream splice acceptor causing insertion of two amino acids predicted to impair oligomerization-dependent activity. This is supported by neuropathological samples showing accumulation of enlarged synaptic vesicles adherent to the plasma membrane consistent with impaired vesicular fission. Two additional individuals with missense variants affecting exon 10a, p.Arg399Trp and p.Gly401Asp, had a similar DEE phenotype. In contrast, one individual with a missense variant affecting exon 10b, p.Pro405Leu, which is less expressed in the brain, had a correspondingly less severe presentation. Thus, we implicate variants affecting exon 10a as causing the severe DEE typically associated with DNM1-related disorders. We highlight the importance of considering relevant isoforms for disease-causing variants as well as the possibility of splice site variants acting through a dominant-negative mechanism.
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