BRPF1 – Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis

BRPF1 is robustly implicated in the pathogenesis of intellectual developmental disorder with dysmorphic facies and ptosis, an autosomal dominant condition. Multiple independent case reports and multi‐patient studies provide convergent clinical data supporting the association, with clear evidence of familial segregation and a consistent constellation of clinical features that include delayed speech, global developmental delay, ptosis, and intellectual disability (PMID:32457794, PMID:35243762).

Genetic evidence shows a strong signal with several variants identified across unrelated probands. Notably, the heterozygous missense variant c.1054G>T (p.Val352Leu) has been reported as a recurring finding in affected individuals, while additional reports describe a spectrum that includes nonsense and frameshift variants. This consistent autosomal dominant inheritance and recurrence of similar mutational mechanisms across studies adds significant weight to the association (PMID:39837771, PMID:32457794).

Detailed segregation analyses in several families have demonstrated that the variant co‐segregates with disease, with additional affected relatives identified in extended pedigrees. In these reports, at least 23 probands and numerous affected relatives were documented, underscoring a clear inheritance pattern and providing robust genetic evidence for the role of BRPF1 in this disorder (PMID:35243762).

Functional studies further support the pathogenicity of BRPF1 variants. Experimental data, including in vitro acetylation assays, animal models, and cellular studies, have shown that disruption of BRPF1 impairs histone acetylation and chromatin remodeling, mechanisms critical for proper neurodevelopment. These studies demonstrate concordance between the molecular dysfunction and the clinical phenotype of intellectual disability and facial dysmorphism (PMID:27939639, PMID:34485298).

While there is minor phenotypic variability—with isolated cases showing features such as normal intellectual development accompanied by congenital ptosis—the overall body of evidence favors a strong gene–disease link. Any occasional discordance does not outweigh the cumulative genetic and functional data supporting BRPF1’s involvement in the disorder.

In conclusion, the integration of genetic, segregation, and functional evidence establishes a strong association between BRPF1 and intellectual developmental disorder with dysmorphic facies and ptosis. This comprehensive understanding supports its use in diagnostic decision‑making and highlights its potential value for targeted therapeutic interventions. Key take‑home: BRPF1 testing should be incorporated into genetic evaluations for patients presenting with developmental delay, ptosis, and dysmorphic facial features.

References

• Frontiers in genetics • 2020 • Novel Missense Variant in Heterozygous State in the BRPF1 Gene Leading to Intellectual Developmental Disorder With Dysmorphic Facies and Ptosis PMID:32457794
• American journal of medical genetics. Part A • 2022 • BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development PMID:35243762
• European journal of medical genetics • 2019 • Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum PMID:31176769
• Clinical genetics • 2025 • The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review PMID:39837771
• American journal of human genetics • 2017 • Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis PMID:27939639

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