BRPF1 was first reported in relation with autosomal dominant syndromic complex neurodevelopmental disorder in 2016, with further supporting evidence from a large case series published in 2024 involving 29 individuals (Colson et al.; PMID: 39837771). Phenotypic features reported in affected individuals include intellectual disability, developmental delay, hypotonia, speech and language delay, and behavioral features such as attention deficit hyperactivity disorder (ADHD), anxiety, and autistic behaviors. Distinct facial features (e.g., ptosis, blepharophimosis, and broad nasal bridge) were consistently reported.
Fourteen variants (frameshift, nonsense, and whole-gene deletions) that have been reported in 22 probands in 2 publications (PMIDs: 27939639 and 39837771) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be haploinsufficiency (PMID:39837771). Splice site variants predicted to result in premature stop codons and variants affecting highly conserved residues further supported the gene-disease relationship.
This gene-disease relationship is also supported by experimental evidence such as animal and cellular models (PMID: 34485298). In mouse models, hippocampal knockdown of Brpf1 led to spatial learning deficits and dysregulation of synaptic genes (e.g., Grin2a, Cxcl10). At the cellular level, knockdown in primary hippocampal neurons reduced mEPSC frequency, indicating impaired excitatory synaptic transmission, and led to altered expression of synaptic regulators (C1ql1, Gpr17), reinforcing the gene’s functional relevance to cognitive processes.
In summary, there is definitive evidence supporting the relationship between BRPF1 and autosomal dominant syndromic 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 Gene Curation Expert Panel on April 15, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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