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.

Keywords: Pediatrics; epilepsy; genetics; nervous System Diseases.

Figure 1

Pedigrees, clinical and genetic characteristics of individuals carrying biallelic variants in DNM1 pedigrees of family 1 (A) and family 2 (B) with pathogenic variants in DNM1. Affected siblings (solid symbols) in both families carry homozygous, truncating variants in DNM1, while non-affected parents are heterozygous carriers of the identified DNM1 variants (white symbols). Non-affected siblings were either homozygous for the WT allele or heterozygous carriers of the identified DNM1 variant. (C) Electropherograms of the identified DNM1 (ENST00000372923.8, NM_004408.3) variants c.97C>T (p.Gln33*) (upper panel) and c.850C>T (p.Gln284*) (lower panel). PCR and subsequent Sanger sequencing confirmed homozygosity of the identified DNM1 variants in both affected individuals and parental heterozygous carrier status. (D) Schematic representation of the DNM1 protein structure with an N-terminal GTPase domain (orange), a middle domain (blue), a pleckstrin homology (PH) domain (green), a GTPase effector domain (grey) and a C-terminal PRD (yellow). Black arrows indicate the localisation of the two truncating variants identified within this study. Localisation of heterozygous missense variants in DNM1 associated in previous studies with DEE are indicated by black asterisks. DEE, developmental and epileptic encephalopathy; GED, PH, PRD Pro-rich domain; WT, wild type.

Figure 2

(A) Axial and sagittal T2-weighted images of subject III.1 from family 1 at the age of 3 months revealing agenesis of the corpus callosum. (B) Axial and sagittal T1 images from subject III.6 from family 2 with mainly frontal brain atrophy, dilated subarachnoid spaced, widened perisylvian fissure and mildly dilated lateral ventricles.