Intellectual disability
Gene: BRF2

BRF2 (BRF2, RNA polymerase III transcription initiation factor subunit)
EnsemblGeneIds (GRCh38): ENSG00000104221
EnsemblGeneIds (GRCh37): ENSG00000104221
OMIM: 607013, Gene2Phenotype
BRF2 is in 5 panels

1 review

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There are 3 unrelated families with biallelic BRF2 variants and syndromic congenital anomalies, including intellectual disability and developmental delay. Hence, this gene can be promoted to Green at the next udpate, which also ensures inclusion on R27 Paediatric disorders.
Created: 27 Mar 2026, 5:27 p.m. | Last Modified: 27 Mar 2026, 5:27 p.m.

Panel Version: 9.355

PMID: 40229899 Mattioli et al., 2025
Report of six families (3 Icelandic, 1 Iranian, 1 Pakistani, 1 of unknown ancestry) with bi-allelic variants in BRF2 presenting with early mortality, brain, and craniofacial anomalies and/or neurodevelopmental disorders (NDD). Patients had phenotypes ranging from perinatal death to Treacher-Collins and craniosynostosis with radial defects and immunodeficiency or global developmental delay, hearing, and vision impairment.
Families 1-3 = Icelandic families with founder BRF2 variant c.214 + 1G > A, not much detail provided on phenotype beyond "early lethality". Genotyping was not done for the affected fetuses, it was inferred from living family members.

Family 4 - female proband with Treacher-Collins syndrome, presented with hearing impairment, soft cleft palate, microcephaly, and facial dysmorphism. She was homozygous for BRF2 c.481G > T; p.(Gly161*).

Family 5 - 2 sibs compound het for BRF2 c.782C > T ; p.(Pro261Leu) & c.404_409delinsA; p.(Met135Asnfs*15);
Patient II:1 female, presented with coronal synostosis, microcephaly, hypertelorism, a small beaked, nose, retrognathia, shortened right radius, and absent left radius, with radial deviation of the hands and contractures of all fingers. She was found to have anemia, leukocytosis, marked eosinophilia, and thrombocytopenia, and developed a significant rash by 1 month of age; she died at 2 mo from bacterial infection.
Patient II:2, male - presented with frontal bone hypoplasia with bilateral coronal synostosis, micrognathia, small orbits, low-set ears, downward slanting palpebral fissures, and significantly decreased B-cell CD19 subsets. He subsequently developed ichthyosiform erythroderma and eosinophilic myeloid hyperplasia. He had developmental and speech delays.

Family 6 - 4 affected sibs with moderate ID, and delays in motor and speech development; 2 sibs had mild hearing and vision impairment. 2 sibs confirmed homozygous for BRF2 c.31G > A; p.(Gly11Ser).

Zebrafish knocked down for the orthologous brf2 presented with abnormal escape response, reduced swimming velocity and head size, and craniofacial malformations. Phenotype was rescued by human BRF2, but not by isoforms with patients variants.

PMID: 40781771 Yoon et al., 2025
Case report of a girl, presumed Korean born to non-consanguineous parents, with multiple congenital anomalies: polydactyly of the right fifth toe, duplex kidney on the right side, hypodontia, and dysmorphic facial features. She had recurrent infections in the neonatal period, and was diagnosed with primary immunodeficiency at 4 months. Mild ID (IQ=60) was diagnosed at age 16 yrs. She harboured comp het BRF2 variants: c.379C>T, p.Arg127Ter & c.782C>T, p.Pro261Leu. Older sister was similarly affected; she died of infection at 19 months.
Single-cell RNA-seq analysis of the patient sample revealed transcriptional abnormalities in PBMCs from the patient harboring BRF2 mutations. BRF2 mutations disrupt RNA Pol III activity specifically at type III promoters, leading to transcriptional dysregulation of critical noncoding RNAs

BRF2 is not yet associated with a phenotype in OMIM (accessed 27 Mar 2026).
Sources: Literature
Created: 27 Mar 2026, 5:24 p.m. | Last Modified: 27 Mar 2026, 5:31 p.m.

Panel Version: 9.355

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042; intellectual disability, MONDO:0001071

Publications

Created: 27 Mar 2026, 5:24 p.m.
Last Modified: 27 Mar 2026, 5:31 p.m.
Panel version: 9.354

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber
Literature

Phenotypes

multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042
intellectual disability, MONDO:0001071

Tags

Q1_26_promote_green

OMIM

607013

Clinvar variants

Variants in BRF2

Penetrance

None

Publications

Panels with this gene

History Filter Activity

27 Mar 2026, Gel status: 2

Entity classified by Genomics England curator

Ida Ertmanska (Genomics England Curator)

Gene: brf2 has been classified as Amber List (Moderate Evidence).

27 Mar 2026, Gel status: 1

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes

Ida Ertmanska (Genomics England Curator)

gene: BRF2 was added gene: BRF2 was added to Intellectual disability. Sources: Literature Q1_26_promote_green tags were added to gene: BRF2. Mode of inheritance for gene: BRF2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BRF2 were set to 40229899; 40781771 Phenotypes for gene: BRF2 were set to multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042; intellectual disability, MONDO:0001071 Review for gene: BRF2 was set to GREEN

Intellectual disability Gene: BRF2