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

Abstract

BackgroundDevelopmental 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.MethodsWe 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.ResultsWe 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.ConclusionOur 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.

Clinical, Radiological, and Genetic Characterization of a Patient with a Novel Homoallelic Loss-of-Function Variant in DNM1

“…They also did not show any genotypic variation in the DNM1 further exemplifying the autosomal recessive mode of transmission for the variant. Of note, as previously reported before, heterozygous knockout mice [ 16 ] as well as heterozygous carriers [ 12 ] are all normal, similar to the parents (heterozygous carriers) reported in our study. Therefore, as emphasized by Yigit et al (2022), haploinsufficiency does not involve in the pathobiological mechanism of DNM1-associated DEE in humans.…”

“…Our patient presented with a global developmental delay, severe hypotonia, notable hyperreflexia, nystagmus, and facial dysmorphism. Moreover, the neuroimaging of our patient showed a global mild volume loss in the cerebral hemispheres with a resultant mild expansion of the lateral ventricles and CSF spaces, in addition to mild agenesis of the corpus callosum, but the rest of the brain was mostly unremarkable, in comparison to Yigit et al (2022) cases [ 12 ]. Interestingly, the novel deletion also resides in the GTPase domain, similar to the other loss-of-function variants reported before [ 8 ].…”

“…Since the first case of a pathogenic DNM1 variant was discovered nearly a decade ago, most of the cases were reported to be in autosomal dominant mode, caused by heterozygous deleterious variants. The only exception to this was the study describing two unrelated DEE cases harboring loss-of-function nonsense variants in a homozygous state [ 12 ]. Interestingly, both nonsense variants in Yigit et al (2022) study caused an immediate stop codons (c.97C>T; p.Gln33* in family 1, and c.850C>T; p.Gln284* in family 2) in DNM1 which led to an early truncation of DNM1.…”

“…DNM1 works by self-assembling into a helical polymer around the vesicle membrane and then constricting after GTP hydrolysis, leading to the fission of the vesicle and complete endocytosis [ 10 , 11 ]. Only recently, homozygous deleterious variants were reported in DNM1 [ 12 ]. Here, we present the third homozygous variant in DNM1 in a female who presented with global developmental delay, myoclonic seizures, facial dysmorphism, and nystagmus.…”

A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism

“…In fact, two human families with homozygous nonsense variants in DNM1 have disease similar to typical DNM1 -related disorders. 45 Thus, a vast majority of DNM1 product in humans and mice must be affected in order to replicate the effects of a single missense variant in human DNM1a, emphasizing the significance of this isoform alone in causing severe disease.…”