Advances in epilepsy associated with 16p11.2 microdeletion syndrome

Abstract

Background: 16p11.2 microdeletion syndrome is a genetic disorder with a population prevalence of approximately 2.84.3 per 100,000 individuals. Epilepsy is one of its core symptoms, significantly impacting neurodevelopment and quality of life. Current treatment strategies are shifting from empirical antiepileptic drug use toward mechanism-based precision therapy. Epilepsy in this syndrome typically presents in infancy, with focal seizures as the most common type.

Methods: Electroencephalogram findings often include focal or multifocal epileptiform discharges. Genomic deletions affecting key genes such as PRRT2, KCTD13, TAOK2, QPRT, and SEZ6L2 contribute to neurodevelopmental abnormalities, synaptic dysfunction, and excitatory-inhibitory imbalance through dysregulated molecular pathways including RhoA signaling, microtubule dynamics, and quinolinic acid metabolism.

Conclusions: Clinically, levetiracetam shows limited efficacy in PRRT2-related epilepsy, whereas valproate, oxcarbazepine, and topiramate are often effective. Emerging therapeutic strategies target specific molecular mechanisms, such as RhoA inhibition or modulation of the kynurenine pathway. The integration of genetic diagnosis with pathway-specific interventions offers promising avenues for improving seizure control and neurodevelopmental outcomes in patients with 16p11.2 microdeletion syndrome. In this article, we review the clinical features.molecular mechanisms and therapeutic strategies of 16p11.2 microdeletion.associated epilepsy to provide a theoretical basis for precision diagnosis and treatment.

Keywords

16p11.2 microdeletion syndrome / epilepsy / mechanism / precision therapy

References

[1] Shinawi M, Liu P, Kang SHL, et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioral problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet. 2010; 47(5): 332-341.

[2] Chung WK, Roberts TP, Sherr EH, et al. 16p11.2 deletion syndrome. Curr Opin Genet Dev. 2021; 68: 49-56.

[3] Tian Y, Shi Z, Cai J, et al. Levetiracetam may be an unsuitable choice for patients with PRRT2-associated self-limited infantile epilepsy. BMC Pediatrics. 2023; 23: 529.

[4] Escamilla CO, Filonova I, Walker AK, et al. Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature. 2017; 551(7679): 227-231.

[5] Scharrenberg R, Richter M, Johanns O, et al. TAOK2 rescues autism-linked developmental deficits in a 16p11.2 microdeletion mouse model. Mol Psychiatry. 2022; 27(11): 4707-4721.

[6] Leone R, Zuglian C, Brambilla R, et al. Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes. Front Pharmacol. 2024; 15:1407865.

[7] Elsayed LEO, Alharbi NA, Alqarni AM, et al. Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy–Walker malformation spectrum: expanding the known phenotype. Hum Genomics. 2024; 18: 95.

[8] Montanucci L, Lewis-Smith D, Collins RL, et al. Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals. Nat Commun. 2023; 14: 4392.

[9] Lai CY, Chen RH, Zhong CL, et al. Clinical phenotype and genetic characterization of 16p11.2 microdeletion-associated epilepsy in children. Chin J Contemp Pediatrics. 2022; 24(5): 585.

[10] Luo G, Chen J, Hou M, et al. Analysis of four cases of chromosome 16p11.2 microdeletion syndrome with epileptic seizure phenotypes. Chinese Pediatric Emergency Medicine. 2024; 31(5): 398-401. https://kns.cnki.net/KCMS/detail/detail.aspx?dbcode=ZHYX&dbname=CJFDZHYX&filename=LYYL202405017

[11] Su HH, Li WH. Research progress on 16p11.2 microdeletion syndrome. International Journal of Pediatrics. 2024; 51(7): 485-488.

[12] HuiHong S. Shui-Zhen Z, Wen-Hui L. Phenotypic and genotypic characterization of typical 16p11.2 deletion syndrome. Chin J Neurol. 2023; 56(9): 1018-1026.

[13] Ping J, Tong Z, Jihong T, et al. De novo mutation of 16p11.2 microdeletion syndrome (with a case report and literature review). Chin Clin Neurosci. 2021; 29(3): 303-309.

[14] Arbogast T, Ouagazzal AM, Chevalier C, et al. Reciprocal effects on neurocognitive and metabolic phenotypes in mouse models of 16p11.2 deletion and duplication syndromes. PLoS Genet. 2016; 12(2):e1005709.

[15] Portmann T, Yang M, Mao R, et al. Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome. Cell Rep. 2014; 7(4): 1077-1092.

[16] Qiu Y, Arbogast T, Lorenzo SM, et al. Oligogenic effects of 16p11.2 copy-number variation on craniofacial development. Cell Rep. 2019; 28(13): 3320-3328.e4.

[17] Ren B, Yan Z. 16p11.2 copy number variations and neurodevelopmental disorders. Trends Neurosci. 2020; 43(11): 886-901. https://pubmed.ncbi.nlm.nih.gov/32993859/

[18] Tan GH, Liu YY, Wang L, et al. PRRT2 deficiency induces paroxysmal kinesigenic dyskinesia by regulating synaptic transmission in cerebellum. Cell Res. 2018; 28(1): 90-110. https://pubmed.ncbi.nlm.nih.gov/29056747/

[19] Valente P, Romei A, Fadda M, et al. Constitutive inactivation of the PRRT2 gene alters short-term synaptic plasticity and promotes network hyperexcitability in hippocampal neurons. Cereb Cortex. 2019; 29(5): 2010-2033.

[20] Franchi F, Marte A, Corradi B, et al. The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na+ channels. J Biol Chem. 2023; 299(5):104632.

[21] Richter M, Murtaza N, Scharrenberg R, et al. Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. Mol Psychiatry. 2019; 24(9): 1329-1350.

[22] Haslinger D, Waltes R, Yousaf A, et al. Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model. Mol Autism. 2018; 9: 56.

[23] Pocivavsek A, Schwarcz R, ES. Neuroactive kynurenines as pharmacological targets: new experimental tools and exciting therapeutic opportunities. Pharmacol Rev. 2024; 76(6): 978.

[24] National Center for Biotechnology Information (2025). PubChem Gene Summary for Gene 26470, SEZ6L2-seizure related 6 homolog like 2 (human). Retrieved September 19, 2025 from https://pubchem.ncbi.nlm.nih.gov/gene/SEZ6L2/human

[25] Fetit R, Price DJ, Lawrie SM, et al. Understanding the clinical manifestations of 16p11.2 deletion syndrome: a series of developmental case reports in children. Psychiatric Genet. 2020; 30(5): 136.

[26] Tai DJC, Razaz P, Erdin S, et al. Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models. Am J Hum Genet. 2022; 109(10): 1789-1813.

[27] Rogawski MA. AMPA receptors as a molecular target in epilepsy therapy. Acta Neurol Scand Suppl. 2013; 2013(197): 9-18.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.