Abstract
Background
Copy number variations (CNVs) are considered to be associated with various neurocognitive disorders, particularly severe pediatric conditions such as intellectual disability and epilepsy. In this study, our aim is to determine the distribution and pathogenicity of CNVs in pediatric epilepsy patients, thereby expanding the spectrum of related syndromes or gene phenotypes, explore potential new epilepsy genes within CNVs.
Methods
We collected clinical data from 425 pediatric epilepsy patients and performed WES, including both pathogenic variant analysis and CNV analysis. Variants were classified per ACMG guidelines. Analyzed the phenotypic characteristics associated with genetic diagnostic results and performed further research and analysis on diagnostic CNVs.
Results
Among the 425 pediatric epilepsy patients, diagnostic SNVs/indels were detected in 104 cases (24.5%). CNV testing revealed 49 cases with diagnostic CNVs (11.5%). For patients with epilepsy phenotypes unexplained by CNVs, two potential epilepsy genes were suggested through analysis.
Conclusion
CNV analysis significantly improves the genetic diagnostic yield in pediatric epilepsy patients, achieving a rate of 11.5%. Patients with developmental delay or cardiopathy are more likely to harbor diagnostic CNVs. In-depth analysis of diagnostic CNVs can identify the genetic etiology in epilepsy patients, guide follow-up strategies, and facilitate the discovery of promising candidate epilepsy genes.
Impact
-
CNV analysis can enhance the molecular diagnostic capability of epilepsy.
-
Patients with developmental delay or cardiac disease are more likely to have diagnostic CNVs.
-
In-depth analysis of CNVs can help uncover potential candidate epilepsy genes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 14 print issues and online access
$259.00 per year
only $18.50 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
References
Fisher, R. S. et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55, 475–82 (2014).
Symonds, J. D. et al. Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants. Brain 144, 2879–2891 (2021).
Wirrell, E. et al. Predictors and course of medically intractable epilepsy in young children presenting before 36 months of age: a retrospective, population-based study. Epilepsia 53, 1563–9 (2012).
Poke, G. et al. Epidemiology of developmental and epileptic encephalopathy and of intellectual disability and epilepsy in children. Neurology 100, e1363–e1375 (2023).
Stodberg, T. et al. Outcome at age 7 of epilepsy presenting in the first 2 years of life. A population-based study. Epilepsia 63, 2096–2107 (2022).
Balestrini, S. et al. The aetiologies of epilepsy. Epileptic Disord. 23, 1–16 (2021).
Symonds, J. D. & McTague, A. Epilepsy and developmental disorders: next generation sequencing in the clinic. Eur. J. Paediatr. Neurol. 24, 15–23 (2020).
Variane, G. et al. Remote monitoring for seizures during therapeutic hypothermia in neonates with hypoxic-ischemic encephalopathy. JAMA Netw. Open 6, e2343429 (2023).
Yuan, H. et al. CNV profiles of Chinese pediatric patients with developmental disorders. Genet. Med. 23, 669–678 (2021).
Mullen, S. A. et al. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 81, 1507–14 (2013).
Zhao, M. et al. Computational tools for copy number variation (CNV) detection using next-generation sequencing data: features and perspectives. BMC Bioinform. 14, S1 (2013).
Zhai, Y. et al. Incorporation of exome-based CNV analysis makes trio-WES a more powerful tool for clinical diagnosis in neurodevelopmental disorders: a retrospective study. Hum. Mutat. 42, 990–1004 (2021).
Fisher, R. S. et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia 58, 531–542 (2017).
Riggs, E. R. et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet. Med. 22, 245–257 (2020).
Afzali, B. et al. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat. Immunol. 18, 813–823 (2017).
van Woerden, G. M. et al. The MAP3K7 gene: further delineation of clinical characteristics and genotype/phenotype correlations. Hum. Mutat. 43, 1377–1395 (2022).
Le Goff, C. et al. Heterozygous mutations in MAP3K7, encoding TGF-beta-activated kinase 1, cause cardiospondylocarpofacial syndrome. Am. J. Hum. Genet. 99, 407–13 (2016).
Edwards, J. J. et al. Systems analysis implicates WAVE2 complex in the pathogenesis of developmental left-sided obstructive heart defects. JACC Basic Transl. Sci. 5, 376–386 (2020).
Traylor, R. N. et al. Microdeletion of 6q16.1 encompassing EPHA7 in a child with mild neurological abnormalities and dysmorphic features: case report. Mol. Cytogenet. 2, 17 (2009).
Levy, J. et al. EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder. Clin. Genet. 100, 396–404 (2021).
Rudd, M. F. et al. Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia. Blood 108, 638–44 (2006).
Shulskaya, M. V. et al. Whole-exome sequencing in searching for new variants associated with the development of Parkinson’s disease. Front. Aging Neurosci. 10, 136 (2018).
Turner, T. N. et al. Sex-based analysis of de novo variants in neurodevelopmental disorders. Am. J. Hum. Genet. 105, 1274–1285 (2019).
Kaplanis, J. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586, 757–762 (2020).
Au, K. S. et al. Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration. Sci. Rep. 11, 3639 (2021).
Fu, J. M. et al. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat. Genet. 54, 1320–1331 (2022).
Xu, B. et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat. Genet. 43, 864–8 (2011).
Ganesh, S. et al. Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes. Psychiatry Clin. Neurosci. 73, 11–19 (2019).
Buonaiuto, S. et al. Prioritization of putatively detrimental variants in euploid miscarriages. Sci. Rep. 12, 1997 (2022).
Villacis, R. et al. Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development. J. Mol. Med. 95, 523–533 (2017).
Servetti, M. et al. Neurodevelopmental disorders in patients with complex phenotypes and potential complex genetic basis involving non-coding genes, and double CNVs. Front. Genet. 12, 732002 (2021).
Fernandez, A. et al. A novel microduplication in INPP5A segregates with schizophrenia spectrum disorder in the family of a patient with both childhood onset schizophrenia and autism spectrum disorder. Am. J. Med. Genet. A 185, 1841–1847 (2021).
Dong, X. et al. Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort. J. Med. Genet. 57, 558–566 (2020).
Kim, S. H. et al. Common genes and recurrent causative variants in 957 Asian patients with pediatric epilepsy. Epilepsia 65, 766–778 (2024).
Rochtus, A. et al. Genetic diagnoses in epilepsy: the impact of dynamic exome analysis in a pediatric cohort. Epilepsia 61, 249–258 (2020).
Zeng, Y. et al. High positive predictive value of CNVs detected by clinical exome sequencing in suspected genetic diseases. J. Transl. Med. 22, 644 (2024).
Rajagopalan, R. et al. A highly sensitive and specific workflow for detecting rare copy-number variants from exome sequencing data. Genome Med. 12, 14 (2020).
Backenroth, D. et al. CANOES: detecting rare copy number variants from whole exome sequencing data. Nucleic Acids Res. 42, e97 (2014).
Rein, B. & Yan, Z. 16p11.2 Copy number variations and neurodevelopmental disorders. Trends Neurosci. 43, 886–901 (2020).
Su, J. et al. de novo interstitial deletions at the 11q23.3-q24.2 region. Mol. Cytogenet. 9, 39 (2016).
Grossfeld, P. D. et al. The 11q terminal deletion disorder: a prospective study of 110 cases. Am. J. Med Genet A 129A, 51–61 (2004).
Ferrario, A. et al. Expanding genotype/phenotype correlation in 2p11.2-p12 microdeletion syndrome. Genes 14, 2222 (2023).
Weaver, K. N. et al. Acrofacial dysostosis, Cincinnati type, a mandibulofacial dysostosis syndrome with limb anomalies, is caused by POLR1A dysfunction. Am. J. Hum. Genet. 96, 765–74 (2015).
Smallwood, K. et al. POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies. Am. J. Hum. Genet. 110, 809–825 (2023).
Panwala, T. F. et al. Childhood-onset hereditary spastic paraplegia (HSP): a case series and review of literature. Pediatr. Neurol. 130, 7–13 (2022).
Coppola, A. et al. Diagnostic implications of genetic copy number variation in epilepsy plus. Epilepsia 60, 689–706 (2019).
Gale, N. W. et al. Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17, 9–19 (1996).
Beuter, S. et al. Receptor tyrosine kinase EphA7 is required for interneuron connectivity at specific subcellular compartments of granule cells. Sci. Rep. 6, 29710 (2016).
Communi, D., Lecocq, R. & Erneux, C. Arginine 343 and 350 are two active residues involved in substrate binding by human type I D-myo-inositol 1,4,5,-trisphosphate 5-phosphatase. J. Biol. Chem. 271, 11676–83 (1996).
Berridge, M. J. The inositol trisphosphate/calcium signaling pathway in health and disease. Physiol. Rev. 96, 1261–96 (2016).
Timms, A. E. et al. Support for the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families. JAMA Psychiatry 70, 582–90 (2013).
Yang, A. W., Sachs, A. J. & Nystuen, A. M. Deletion of Inpp5a causes ataxia and cerebellar degeneration in mice. Neurogenetics 16, 277–85 (2015).
Liu, Q. et al. Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17. Nat. Commun. 11, 1101 (2020).
Acknowledgements
We gratefully acknowledge the kind cooperation and agreement of patients and their parents.
Funding
This work was supported by the Public Health and Technology Project of Tianjin (TJWJ2024QN078), the Program of Tianjin Science and Technology Plan (23JCQNJC01610) and the Program of Tianjin Science and Technology Plan (23JCQNJC01600).
Author information
Authors and Affiliations
Contributions
Z.S.Y.: writing-original draft, sequencing data analysis. W.X.T.: writing-review & editing, funding acquisition. M.J.: clinical data collection and writing. L.J.C.:clinical data collection. D.Y.:clinical data collection. L.D.: project administration, funding acquisition. S.J.B.: methodology, project administration, funding acquisition. C.C.Q.: supervision, project administration, funding acquisition.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Consent statement
Informed consent for genetic analyses was obtained for all individuals, and genetic studies were performed as approved by the Ethics and Human Commit.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhang, S., Wang, X., Meng, J. et al. The utility of CNV analysis in identifying the molecular etiology of pediatric epilepsy patients. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04427-w
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41390-025-04427-w
