Dataset Information

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

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.

SUBMITTER: Yigit G

PROVIDER: S-EPMC9132866 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Loss-of-function variants in <i>DNM1</i> cause a specific form of developmental and epileptic encephalopathy only in biallelic state.

Yigit Gökhan G Sheffer Ruth R Daana Muhannad M Li Yun Y Kaygusuz Emrah E Mor-Shakad Hagar H Altmüller Janine J Nürnberg Peter P Douiev Liza L Kaulfuss Silke S Burfeind Peter P Wollnik Bernd B Brockmann Knut K

Journal of medical genetics 20210625 6

<h4>Background</h4>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 <i>DNM1</i>.<h4>Methods</h4>We performed a detailed clinical characterisation of tw ...[more]

PMID: 34172529

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