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Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

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Item Type:Article
Title:Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state
Creators Name:Yigit, G., Sheffer, R., Daana, M., Li, Y., Kaygusuz, E., Mor-Shakad, H., Altmüller, J., Nürnberg, P., Douiev, L., Kaulfuss, S., Burfeind, P., Wollnik, B. and Brockmann, K.
Abstract:BACKGROUND: Developmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1. METHODS: We performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families. RESULTS: We excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE. CONCLUSION: Our finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1. All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance.
Keywords:Brain Diseases, Heterozygote, Missense Mutation, Mutation, Whole Exome Sequencing
Source:Journal of Medical Genetics
ISSN:0022-2593
Publisher:BMJ Publishing Group
Volume:59
Number:6
Page Range:549-553
Date:20 May 2022
Official Publication:https://doi.org/10.1136/jmedgenet-2021-107769
PubMed:View item in PubMed

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