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

Yigit, Gokhan, Sheffer, Ruth, Daana, Muhannad, Li, Yun, Kaygusuz, Emrah, Mor-Shakad, Hagar, Altmueller, Janine, Nuernberg, Peter, Douiev, Liza ORCID: 0000-0001-5120-698X, Kaulfuss, Silke ORCID: 0000-0003-2577-9711, Burfeind, Peter, Wollnik, Bernd ORCID: 0000-0003-2589-0364 and Brockmann, Knut . Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state. J. Med. Genet.. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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DOI:10.1136/jmedgenet-2021-107769

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.

Item Type:

Journal Article

Creators:

Creators	Email	ORCID	ORCID Put Code
Yigit, Gokhan	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Sheffer, Ruth	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Daana, Muhannad	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Li, Yun	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Kaygusuz, Emrah	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Mor-Shakad, Hagar	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Altmueller, Janine	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Nuernberg, Peter	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Douiev, Liza	UNSPECIFIED	orcid.org/0000-0001-5120-698X	UNSPECIFIED
Kaulfuss, Silke	UNSPECIFIED	orcid.org/0000-0003-2577-9711	UNSPECIFIED
Burfeind, Peter	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED
Wollnik, Bernd	UNSPECIFIED	orcid.org/0000-0003-2589-0364	UNSPECIFIED
Brockmann, Knut	UNSPECIFIED	UNSPECIFIED	UNSPECIFIED