Authors :
Presenting Author: Agilda Dema, DO – University of Chicago
Nitya Beriwal, MD – University of Chicago
Sho Yano, MD – University of Chicago
Douglas Nordli, MD – University of Chicago
Rationale:
BRPF1-related epilepsy is an exceedingly rare neurodevelopmental disorder caused by pathogenic variants in the BRPF1 gene, which encodes a chromatin regulator essential for neural development and epigenetic control[1]. Because so few cases have been described, its clinical and electrophysiological features remain scant. As a result, highlighting potential EEG biomarkers—such as pleomorphic centrotemporal spikes, which are also seen in Rett syndrome, Fragile X syndrome, and GRIN2A-related epilepsies—may enhance global recognition, improve diagnostic validity, and shed light on shared pathophysiological mechanisms across genetic epilepsies. Detailed EEG phenotyping is therefore critical both to distinguish BRPF1-related epilepsy from more benign syndromes (e.g., SeLECTS) and to identify robust biomarkers for this and other rare genetic epilepsies.Methods:
We conducted a detailed clinical and neurophysiological evaluation of a 3-year-old girl with global developmental delay, epilepsy, and a de novo BRPF1 nonsense variant.Results:
In both the initial and follow-up EEGs, we observed abundant, atypical centrotemporal spikes that were uniquely asynchronous and often exhibited a “volleying” pattern. These discharges consistently co-occurred with left posterior temporal slowing and a sharply contoured, high-voltage, disorganized mu rhythm. The persistence of these distinctive features across recordings underscores their potential as syndrome-specific EEG biomarkers for BRPF1-related epilepsy.
Whole-exome sequencing identified a heterozygous pathogenic nonsense variant, NM_001003694.1:c.199C >T, p.(Q67*), in BRPF1, consistent with autosomal-dominant BRPF1-related epilepsy. This premature stop codon in exon 2 of 14 predicts loss-of-function due to nonsense-mediated decay or protein truncation, a well-established pathogenic mechanism in BRPF1 disorders[2].Conclusions:
This report of a 3-year-old girl with a novel BRPF1 nonsense variant (c.199C >T, p.(Q67*)) highlights distinctive, asynchronously “volleying” centrotemporal spikes, disorganized high-voltage mu rhythm, and persistent left posterior temporal slowing as potential syndrome-specific EEG biomarkers. These electrographic signatures mirror patterns seen in other genetic epilepsies and remained refractory to antiseizure therapy, underscoring their diagnostic value. Recognizing such features in children with developmental delay and epilepsy can expedite targeted genetic testing, refine prognostic counseling, and inform personalized treatment choices. Integrating genetic findings with neurophysiological markers will enhance accuracy and advance our understanding of rare developmental and epileptic encephalopathies.
References:
1. Yan K, Rousseau J, Littlejohn RO, et al. Mutations in the chromatin regulator gene BRPF1 cause syndromic intellectual disability and deficient histone acetylation. Am J Hum Genet. 2017 Jan 5;100(1):91-104. doi: 10.1016/j.ajhg.2016.11.011. PMID: 27939640.
2. Colson C,Tessarech M, Boucher-Brischoux E, et al. The phenotypic and genotypic spectrum of BRPF1-related disorder: 29 new patients and literature review. Clin Genet. 2025 May;107(5):527-40. doi: 10.1111/cge.14688. Epub 2024 Dec 29. PMID: 39837771.Funding: N/A