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
| Autor: | Corrado Romano, Pinella Failla, Lucia Grillo, Donatella Greco, Martina Miceli, Francesco Calì, Eliana Salvo, Marco Fichera, Ornella Galesi, Lucia Saccuzzo, Carmelo Amato, Maurizio Elia, Lucia Castiglia |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Microcephaly Chromosomal Proteins Non-Histone Biology Gene mutation Bioinformatics Quadriplegia Short stature Chromatin remodeling 03 medical and health sciences Genetics medicine Missense mutation Humans Child Exome Genetics (clinical) 030304 developmental biology 0303 health sciences 030305 genetics & heredity Genetic Diseases Inborn Infant Newborn Infant DNA Methylation medicine.disease Chromatin Assembly and Disassembly Human genetics Actins Chromatin Pedigree DNA-Binding Proteins Neurodevelopmental Disorders Child Preschool Cerebellar atrophy Female medicine.symptom Spasms Infantile |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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