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Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders

Genetics in medicine. 2025 Apr ; 27 (4) : 101251. [epub] 20240917

Genet Med
ISSN 1530-0366 | 1098-3600
Source

Language English Country United States Media print-electronic

Document type Journal Article

Persistent link https://www.medvik.cz/link/pmid39275948

PubMed 39275948
DOI 10.1016/j.gim.2024.101251
PII: S1098-3600(24)00185-0
Knihovny.cz E-resources

Keywords
ACTL6B, Autism, BAFopathies, Epileptic-dyskinetic encephalopathy, Ribosomopathies,
MeSH
Child MeSH
Genes, Dominant MeSH
Phenotype MeSH
Genes, Recessive MeSH
Nuclear Proteins * genetics MeSH
Infant MeSH
Humans MeSH
Intellectual Disability genetics pathology MeSH
Adolescent MeSH
Brain pathology MeSH
Mutation MeSH
Brain Diseases * genetics pathology MeSH
Neurodevelopmental Disorders * genetics MeSH
Child, Preschool MeSH
Developmental Disabilities * genetics pathology MeSH
Check Tag
Child MeSH
Infant MeSH
Humans MeSH
Adolescent MeSH
Male MeSH
Child, Preschool MeSH
Female MeSH
Publication type
Journal Article MeSH
Names of Substances
Nuclear Proteins * MeSH

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of "ribosomopathies."

Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders

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