Document Type
Article
Publication Date
4-14-2025
Identifier
DOI: 10.1186/s13073-025-01463-3; PMCID: PMC11995667
Abstract
BACKGROUND: Variants in genes encoding multiple subunits of the RNA Polymerase III complex which synthesizes rRNAs, tRNAs, and other small RNAs were previously associated with neurological disorders, such as syndromic hypomyelination leukodystrophies, pontocerebellar hypoplasia, and cerebellofaciodental syndrome. One new such candidate is BRF2, which encodes a TFIIB-like factor that recruits the RNA polymerase III complex to type 3 promoters to initiate transcription of U6, RnaseP, and 7SK RNAs.
METHODS: We combined sequencing with functional analyses to investigate the effects of BRF2 variants.
RESULTS: We observe that a previously reported significant underrepresentation of double transmission of a splice variant results in recessive lethality in three large Icelandic families with multiple perinatal losses. Using data aggregation, we identified an additional seven individuals worldwide from three unrelated families carrying biallelic variants in BRF2. Affected individuals present a variable phenotype ranging from severe craniofacial anomalies with early death to intellectual disability with motor and speech development. In silico 3D modelling and functional analyses showed functional impairment of the identified variants, e.g., differences in target loci occupancy. Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. These defects were complemented by the human wild-type but not mutated BRF2 mRNA further demonstrating their deleteriousness.
CONCLUSIONS: Overall, our results support the association of biallelic BRF2 variants with a novel neurodevelopmental disease and provide an additional link between RNA polymerase III, its targets and craniofacial anomalies.
Journal Title
Genome Med
Volume
17
Issue
1
First Page
38
Last Page
38
MeSH Keywords
Humans; Zebrafish; Craniofacial Abnormalities; Animals; Female; Male; Alleles; Perinatal Death; Pedigree; Phenotype; Mutation
PubMed ID
40229899
Keywords
Autosomal recessive; BRF2; Craniofacial anomalies; RNA polymerase III
Recommended Citation
Mattioli F, Friðriksdóttir R, Hebert A, et al. Bi-allelic variants in BRF2 are associated with perinatal death and craniofacial anomalies. Genome Med. 2025;17(1):38. Published 2025 Apr 14. doi:10.1186/s13073-025-01463-3
Comments
Grants and funding
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Publisher's Link: https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-025-01463-3