Submission Details

POU3F3 (also known as BRN1) was first reported in relation to an autosomal dominant complex neurodevelopmental disorder, also called Snijders Blok-Fisher Syndrome, in 2019 (Snijders et al., PMID: 31303265). POU3F3 only has one coding exon. Probands with variants in POU3F3 are characterized mainly by global developmental delay/intellectual disability, impaired speech and language acquisition, and hypotonia. Additional features can include dysmorphisms, gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Nine variants (3 missense, 1 in-frame indel, 1 nonsense, 4 frameshift) that have been reported in 10 probands in 3 publications (PMIDs: 31303265, 33645921, 37165752) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In most of the reported patients, purported truncating variants were detected but missense variants have also been reported in the POU-S and POU-H domains. Functional assays showed truncating variants affected subcellular localization, dimerization, and transcriptional activation while some missense variants showed decreased or increased transcriptional activation in a luciferase assay. The mechanism of pathogenicity is consistent with loss-of-function although the mechanism for several missense variants is unclear and requires further investigation.

There is no scorable experimental evidence to support this gene-disease relationship. Expression studies have demonstrated expression in the neocortex but were not scored per the Intellectual Disability and Autism GCEP’s guidelines on not scoring expression because most genes are expressed in the brain. Additionally, complete homozygous pou3f3 (Brn1) knockout mouse embryos showed disorganized cortical lamination while heterozygous knockout mice showed no clinical features (PMID: 11859196). Brain structural aberrations such as dilation of ventricles, thin corpus callosum, and cerebral atrophy were observed in some patients affected by this disorder. However, due to lack of specificity in the phenotypic overlap and construct validity, the mice are homozygous and humans are heterozygous, this mouse model was not scored.

In summary, there is definitive evidence supporting the relationship between POU3F3 and an autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on June 13, 2024 (SOP Version 10).