Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy.
Marco FicheraPinella FaillaLucia SaccuzzoMartina MiceliEliana SalvoLucia CastigliaOrnella GalesiLucia GrilloFrancesco CalìDonatella GrecoCarmelo AmatoCorrado RomanoMaurizio EliaPublished in: Human genetics (2019)
Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene-disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.
Keyphrases
- early onset
- copy number
- genome wide
- intellectual disability
- drug resistant
- resting state
- late onset
- dna methylation
- white matter
- functional connectivity
- end stage renal disease
- autism spectrum disorder
- multidrug resistant
- photodynamic therapy
- chronic kidney disease
- ejection fraction
- dna damage
- acinetobacter baumannii
- transcription factor
- cerebral ischemia
- newly diagnosed
- gene expression
- peritoneal dialysis
- systematic review
- high throughput
- genome wide identification
- machine learning
- cord blood
- working memory
- patient reported outcomes
- subarachnoid hemorrhage
- drug induced
- single cell
- oxidative stress
- blood brain barrier
- high resolution
- single molecule
- data analysis
- mass spectrometry
- cystic fibrosis
- artificial intelligence
- patient reported
- circulating tumor