Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Detecting genomic mosaicism in “de novo” genetic epilepsy by amplicon-based deep sequencing

Journal of Human Genetics volume 68, pages 73–80 (2023)Cite this article

Subjects

Abstract

Aim

To investigate the occurrence of mosaicism in epilepsy probands and their parents using amplicon-based deep sequencing (ADS).

Methods

Patients were recruited from the outpatient of Peking University First Hospital. Two hundred and sixty-four probands with pathogenic variants tested by next-generation sequencing (NGS) were enrolled.

Results

Mosaic variants were detected in seventeen disease-associated genes from 20 probands, 5 paternal, and 6 maternal parents. The frequency of mosaicism was 11.74% (31/264). Mosaicism in 11 genes was identified from 20 probands with the mutant allelic fractions (MAFs) of 12.95–38.00% in autosomal dominant genes. Five paternal mosaicisms were identified in genes with a MAF of 6.30–20.99%, and six maternal mosaic individuals with a MAF of 2.07–21.90%. Only four mosaic parents had milder seizure history. The affected sibling had the same phenotype consistent with that of the proband, who inherited the variant of SLC1A2 or STXBP1 from their unaffected mosaic mothers, respectively.

Interpretation

Mosaic phenomenon is not rare in families with epilepsy. Phenotypes of mosaic parents were milder or normal. Mosaicism detection is helpful to identify the mutation origin and it provides a theoretical basis for prenatal diagnosis of family reproduction. ADS is a reliable way of mosaicism detection for clinical application.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Dou Y, Yang X, Li Z, Wang S, Zhang Z, Ye AY, et al. Postzygotic single-nucleotide mosaicisms contribute to the etiology of autism spectrum disorder and autistic traits and the origin of mutations. Hum Mutat. 2017;38:1002–13.

    Article  CAS  Google Scholar 

  2. Acuna-Hidalgo R, Bo T, Kwint MP, van de Vorst M, Pinelli M, Veltman JA, et al. Post-zygotic point mutations are an underrecognized source of de novo genomic variation. Am J Hum Genet. 2015;97:67–74.

    Article  CAS  Google Scholar 

  3. Xu X, Yang X, Wu Q, Liu A, Yang X, Ye AY, et al. Amplicon resequencing identified parental mosaicism for approximately 10% of “de novo” SCN1A mutation in children with Dravet Syndrome. Hum Mutat. 2015;36:861–72.

    Article  Google Scholar 

  4. Liu A, Xu X, Yang X, Jiang Y, Yang Z, Liu X, et al. The clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population. Clin Genet [Internet]. 2016;91:54–62. https://doi.org/10.1111/cge.12846.

    Article  CAS  Google Scholar 

  5. Jdila MB, Issa AB, Khabou B, Rhouma BB, Kamoun F, Ammar-Keskes L, et al. Novel mutations in the CDKL5 gene in complex genotypes associated with West syndrome with variable phenotype: First description of somatic mosaic state. Clin Chim Acta [Internet]. 2017;473:51–9. https://doi.org/10.1016/j.cca.2017.08.001.

    Article  CAS  Google Scholar 

  6. Olson HE, Tambunan D, Lacoursiere C, Goldenberg M, Pinsky R, Martin E, et al. Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome. Am J Med Genet Part A. 2015;167:2017–25.

    Article  CAS  Google Scholar 

  7. Zhang Q, Yang X, Wang J, Li J, Wu Q. Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort. Genet Med [Internet]. 2019;21:2–10. https://doi.org/10.1038/s41436-018-0348-2.

    Article  CAS  Google Scholar 

  8. Nathan N, Keppler-Noreuil KM, Biesecker LG, Moss J, Darling TN. Mosaic disorders of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway. Dermatol Clin [Internet]. 2017;35:51–60. https://doi.org/10.1016/j.det.2016.07.001.

    Article  CAS  Google Scholar 

  9. Yang X, Liu A, Xu X, Yang X, Zeng Q, Ye AY, et al. Genomic mosaicism in paternal sperm and multiple parental tissues in a Dravet syndrome cohort. Sci Rep [Internet]. 2017;7:15677. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688122/.

    Article  Google Scholar 

  10. Yang X, Yang X, Chen J, Li S, Zeng Q, Huang AY, et al. ATP1A3 mosaicism in families with alternating hemiplegia of childhood. Clin Genet. 2019;96:43–52.

    Article  CAS  Google Scholar 

  11. Xu X, Yang X, Wu Q, Liu A, Yang X, Ye AY, et al. Amplicon resequencing identified parental mosaicism for approximately 10% of “de novo” SCN1A mutations in children with Dravet Syndrome. Hum Mutat. 2015;36:861–72.

    Article  Google Scholar 

  12. Liu A, Yang X, Yang X, Wu Q, Zhang J, Sun D, et al. Mosaicism and incomplete penetrance of PCDH19 mutations. J Med Genet. 2018;56:81–8.

    Article  Google Scholar 

  13. Campbell IM, Yuan B, Robberecht C, Pfundt R, Szafranski P, Mcentagart ME, et al. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am J Hum Genet. 2014;95:173–82.

    Article  CAS  Google Scholar 

  14. Depienne C, Arzimanoglou A, Trouillard O, Fedirko E, Baulac S. Parental mosaicism can cause recurrent transmission of SCN1A mutations associated with severe myoclonic epilepsy of infancy. Hum Mutat. 2006;27:389.

    Article  Google Scholar 

  15. Chen WW, Balaj L, Liau LM, Samuels ML, Kotsopoulos SK, Maguire CA, et al. BEAMing and droplet digital PCR analysis of mutant IDH1 mRNA in glioma patient serum and cerebrospinal fluid extracellular vesicles. Mol Ther Nucleic Acids. 2013;2:e109.

    Article  Google Scholar 

  16. Myers CT, Hollingsworth G, Muir AM, Schneider AL, Knupp ZTA, King C. Parental mosaicism in “ de novo” epileptic encephalopathies. N Engl J Med. 2018;378:1646–8.

    Article  Google Scholar 

  17. Stosser MB, Lindy AS, Butler E, Retterer K, Piccirillo-Stosser CM, Richard G, et al. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet Med [Internet]. 2017;00:1–8. http://www.nature.com/doifinder/10.1038/gim.2017.114.

    Google Scholar 

  18. Gambin T, Liu Q, Karolak JA, Grochowski CM, Xie NG, Wu LR, et al. Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions. Genet Med. 2020;Online ahe(0).

  19. Weckhuysen S, Mandelstam S, Suls A, Audenaert D, Deconinck T, Claes LRF, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol. 2012;71:15–25.

    Article  CAS  Google Scholar 

  20. Milh M, Lacoste C, Cacciagli P, Abidi A, Sutera-Sardo J, Tzelepis I, et al. Variable clinical expression in patients with mosaicism for KCNQ2 mutations. Am J Med Genet Part A. 2015;167:2314–8.

    Article  CAS  Google Scholar 

  21. Zerem A, Lev D, Blumkin L, Goldberg-Stern H, Michaeli-Yossef Y, Halevy A, et al. Paternal germline mosaicism of a SCN2A mutation results in Ohtahara syndrome in half siblings. Eur J Paediatr Neurol. 2014;18:567–71.

    Article  Google Scholar 

  22. Samuels ME, Friedman JM. Genetic mosaics and the germ line lineage. Genes (Basel). 2015;6:216–37.

    Article  CAS  Google Scholar 

  23. Huang AY, Xu X, Ye AY, Wu Q, Yan L, Zhao B, et al. Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals. Cell Res [Internet]. 2014;24:1311–27. https://doi.org/10.1038/cr.2014.131.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients and their family members for taking part in this study. This study was supported by the Key Research Project of the Ministry of Science and Technology of China (Grant No. 2016YFC0904400 and 2016YFC0904401). We would like to thank Dr. Jiapeng Zhou and Dr. Xiaodong Wang for their assistance in editing the manuscript.

Author information

Author notes

  1. These authors contributed equally: Jiaoyang Chen, Yi Chen.

Authors and Affiliations

  1. Department of Pediatrics and Pediatric Epilepsy Center, Peking University First Hospital, Beijing, 100034, China

    Jiaoyang Chen, Yi Chen, Ying Yang, Xueyang Niu, Jing Zhang, Qi Zeng, Aijie Liu, Xiaojing Xu, Shupin Li, Xiaoling Yang & Yuehua Zhang

  2. Center for Bioinformatics, Peking University, Beijing, 100871, China

    Xiaoxu Yang

  3. Department of Neurology, National Epilepsy Center, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, 201102, China

    Yi Wang

Authors
  1. Jiaoyang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xueyang Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qi Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aijie Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaojing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaoxu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shupin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiaoling Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yuehua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuehua Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

This study was approved by the ethics committee of Peking University First Hospital and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, J., Chen, Y., Yang, Y. et al. Detecting genomic mosaicism in “de novo” genetic epilepsy by amplicon-based deep sequencing. J Hum Genet 68, 73–80 (2023). https://doi.org/10.1038/s10038-022-01103-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-022-01103-3

Search

Advanced search

Quick links