Whole-exome sequencing identifies a novel de novo mutation in DYNC1H1 in epileptic encephalopathies

Abstract

Epileptic encephalopathies (EE) are a group of severe childhood epilepsy disorders characterized by intractable seizures, cognitive impairment and neurological deficits. Recent whole-exome sequencing (WES) studies have implicated significant contribution of de novo mutations to EE. In this study, we utilized WES for identifying causal de novo mutations in 4 parent-offspring trios affected by West syndrome. As a result, we found two deleterious de novo mutations in DYNC1H1 and RTP1 in two trios. Expression profile analysis showed that DYNC1H1 and RTP1 are expressed in almost all brain regions and developmental stages. Interestingly, co-expression and genetic interaction network analyses suggested that DYNC1H1 and RTP1 are tightly associated with known epilepsy genes. Furthermore, we observed that the de novo mutations of DYNC1H1 were identified in several different neuropsychiatric disorders including EE, autism spectrum disorders and intellectual disabilities by previous studies, and these mutations primarily occurred in the functional domain of the protein. Taken together, these results demonstrate DYNC1H1 as a strong candidate and RTP1 as a potential candidate on the onset of EE. In addition, this work also proves WES as a powerful tool for the molecular genetic dissection of children affected by sporadic EE.

A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy

“…Moreover, due to the early mortality, it is uncertain if epilepsy, movement disorders of other neurological phenotypes would have emerged if our patients survived past the neonatal period. This is not dissimilar to other neurological diseases, where the phenotypic expansions have been substantial compared with the initial disease descriptions, for example, DYNC1H1 mutations are associated with Charcot Marie Tooth disease, intellectual disability, epileptic encephalopathy, spinal muscular atrophy with lower extremities dominance (SMA-LED) and spastic paraplegia,31 while BICD2 mutations are associated with lethal arthrogryposis, SMA-LED and spastic paraplegia 32…”

“…The severity of these cases is surprising given the phenotypes reported previously for patients harbouring bi-allelic null UBA5 variants. Although it is not unusual for there to be a wide phenotypic spectrum associated with neurogenetic disease genes,31 even within the same family or across patients harbouring the same disease-causing variant. The clinical signs described are definitive for peripheral nervous system involvement and would not be explained by a central nervous system (CNS) disease.…”

Somatic SLC35A2 mosaicism correlates with clinical findings in epilepsy brain tissue

“…De novo variants in DYNC1H1 have been identified in individuals with malformations of cortical development and in individuals with epileptic encephalopathies, including West syndrome. 21,22 Because of the inherited status of this variant, we do not believe that it is associated with the patient's phenotype and assessed it as a VUS. Our analysis of acquired, somatic variants revealed 46 variants that met the initial filtering criteria, but after manually reviewing these in the IGV to discount strand bias or other sequencing artifacts, we determined that 41/46 suspect variants were sequencing artifacts.…”

ASD and ADHD have a similar burden of rare protein-truncating variants

“…Our second result, DYNC1H1, had 8 case PTVs (4 ASD without ID, 2 ASD with ID, 1 ASD+ADHD with ID, 1 ADHD without ID) and has also been implicated in neurological disorders 21 . Among genes with a p value of less than 0.01, we observed three genes previously associated with ASD by Sanders et al (2015) 14 -POGZ, SCN2A, and ANK2.…”