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| Primary immunodeficiency or monogenic inflammatory bowel disease v8.91 | BRF2 | Ida Ertmanska Phenotypes for gene: BRF2 were changed from to multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v8.90 | BRF2 | Ida Ertmanska Classified gene: BRF2 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v8.90 | BRF2 | Ida Ertmanska Added comment: Comment on list classification: There are 4 individuals from 2 unrelated families with biallelic BRF2 variants and multiple non-specific congential anomalies, including primary immunodeficiency leading to early death. Early lethality was also seen in several Icelandic families with a BRF2 founder variant, though cause of death was not ascertained in those cases. Based on available evidence, this gene can only be rated Amber on this panel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v8.90 | BRF2 | Ida Ertmanska Gene: brf2 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v8.89 | BRF2 | Ida Ertmanska Tag Q1_26_promote_green was removed from gene: BRF2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v8.89 | BRF2 |
Ida Ertmanska gene: BRF2 was added gene: BRF2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. 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 Review for gene: BRF2 was set to GREEN Added comment: 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 - girl 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 Sources: Literature |
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