Objective: To report a novel genotype-phenotype correlation involving a partial duplication of the NBEA gene in a patient presenting with chorea.

Background: NBEA has been identified as a causative gene in neurodevelopmental disorders with or without generalized epilepsy (NEDEGE) and paroxysmal kinesigenic dyskinesia. NEDEGE typically presents with early childhood onset generalized or mixed epilepsy, frequently characterized by myoclonic seizures. While most reported mutations are de novo, copy number variations such as duplications present a complex scenario for interpreting genetic disorders.

Method: We evaluated a 15-year-old patient presenting with progressive, involuntary, irregular limb and facial movements. Clinical evaluation included cranial magnetic resonance imaging (MRI) and a 24-hour ambulatory electroencephalogram (EEG) to assess structural brain damage and overt epilepsy. Genetic screening was conducted using whole-genome sequencing and confirmed by copy number variation sequencing (CNVseq). Segregation analysis was performed within the family.

Results: Clinical evaluation revealed upper limb myoclonus without ataxia, occasional compulsive behaviors, and facial grimacing. The patient had normal cognitive and speech functions, and a history of normal developmental milestones. Cranial MRI and 24-hour ambulatory EEG showed no abnormalities[figure 1]. Whole-genome sequencing and CNVseq identified a partial duplication in NBEA[figure 1] spanning the first 34 exons and part of intron 35[figure 2]. Segregation analysis demonstrated inheritance from the patient’s asymptomatic father[figure 3], indicating incomplete penetrance. Treatment with tiapride led to an improvement in chorea symptoms.

Conclusion: This partial duplication of NBEA appears to maintain the gene’s structural integrity but may alter how the gene interacts with regulatory elements. Unlike typical truncating mutations, this may result in haploinsufficiency with a milder effect. This case suggests a novel genotype-phenotype correlation for NBEA duplications, highlighting the need for further functional studies.

Fig 1. Proband’s CNVseq and brain MRI.

Fig 2. Schematic of duplicated genomic regions.

Fig 3. CNVseq of the proband’s father.

References: 1.Mulhern MS, Stumpel C, Stong N, Brunner HG, Bier L, Lippa N, et al. NBEA: Developmental disease gene with early generalized epilepsy phenotypes. Ann Neurol. 2018;84(5):788-795.
2.Yang JH, Hansen AS. Enhancer selectivity in space and time: from enhancer-promoter interactions to promoter activation. Nat Rev Mol Cell Biol. 2024;25(7):574-591.
3.Pang B, van Weerd JH, Hamoen FL, Snyder MP. Identification of non-coding silencer elements and their regulation of gene expression. Nat Rev Mol Cell Biol. 2023;24(6):383-395.
4.Wang X, Herberg FW, Laue MM, Wullner C, Hu B, Petrasch-Parwez E, et al. Neurobeachin: A protein kinase A-anchoring, beige/Chediak-higashi protein homolog implicated in neuronal membrane traffic. J Neurosci. 2000;20(23):8551-8565.

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/partial-duplication-of-nbea-in-a-patient-presenting-chorea-with-incomplete-penetrance/