Skip to main content
SpringerLink
Log in

Genetic etiologies associated with infantile hydrocephalus in a Chinese infantile cohort

  • Original Article
  • Published:
World Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Background

Infantile hydrocephalus (IHC) is commonly related to other central nervous system diseases, which may have adverse effects on prognosis. The causes of IHC are heterogeneous, and the genetic etiologies are not fully understood. This study aimed to analyze the genetic etiologies of an IHC cohort.

Methods

The data for 110 IHC patients who had received exome sequencing at the Clinical Genetic Center of the Children’s Hospital of Fudan University between 2016 and 2019 were reviewed and analyzed retrospectively. An exome-wide association analysis (EWAS) was performed within this cohort using IHC as the study phenotype.

Results

Of the 110 IHC patients, a pathogenic or likely pathogenic variant was identified in 16 (15%) patients, spanning 13 genes. The genes were mainly associated with metabolic disorders, brain abnormalities, and genetic syndromes. IHC patients who had unclear clinical etiology were more likely to possess a genetic etiology. Based on previous studies and on our EWAS results, ZEB1, SBF2, and GNAI2 were over-represented among IHC patients and might affect the signaling pathways involved in IHC formation.

Conclusions

Our study showed heterogeneous genetic etiologies in an IHC cohort. It is essential to perform genetic testing on IHC patients who have unclear clinical etiology, and genes associated with metabolic disorders, brain abnormalities, and genetic syndromes should be noted. In addition, when aiming to discover IHC susceptibility genes, genes that might influence the signaling pathways involved in IHC formation should be prioritized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Munch TN, Rostgaard K, Rasmussen MLH, Wohlfahrt J, Juhler M, Melbye M. Familial aggregation of congenital hydrocephalus in a nationwide cohort. Brain. 2012;135:2409–15.

    Article  Google Scholar 

  2. Wright Z, Larrew TW, Eskandari R. Pediatric hydrocephalus: current state of diagnosis and treatment. Pediatr Rev. 2016;37:478–90.

    Article  Google Scholar 

  3. Gmeiner M, Wagner H, Zacherl C, Polanski P, Auer C, van Ouwerkerk WJR, et al. Long-term mortality rates in pediatric hydrocephalus-a retrospective single-center study. Childs Nerv Syst. 2017;33:101–9.

    Article  Google Scholar 

  4. Kousi M, Katsanis N. The genetic basis of hydrocephalus. Annu Rev Neurosci. 2016;39:409–35.

    Article  CAS  Google Scholar 

  5. Adle-Biassette H, Saugier-Veber P, Fallet-Bianco C, Delezoide AL, Razavi F, Drouot N, et al. Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases. Acta Neuropathol. 2013;126:427–42.

    Article  CAS  Google Scholar 

  6. Drielsma A, Jalas C, Simonis N, Désir J, Simanovsky N, Pirson I, et al. Two novel CCDC88C mutations confirm the role of DAPLE in autosomal recessive congenital hydrocephalus. J Med Genet. 2012;49:708–12.

    Article  CAS  Google Scholar 

  7. Ekici AB, Hilfinger D, Jatzwauk M, Thiel CT, Wenzel D, Lorenz I, et al. Disturbed Wnt signalling due to a mutation in CCDC88C causes an autosomal recessive non-syndromic hydrocephalus with medial diverticulum. Mol Syndromol. 2010;1:99–112.

    Article  CAS  Google Scholar 

  8. Saillour Y, Zanni G, Des Portes V, Heron D, Guibaud L, Iba-Zizen MT, et al. Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia. J Med Genet. 2007;44:739–44.

    Article  CAS  Google Scholar 

  9. Verhagen JMA, Schrander-Stumpel CTRM, Krapels IPC, de Die-Smulders CEM, van Lint FHM, Willekes C, et al. Congenital hydrocephalus in clinical practice: a genetic diagnostic approach. Eur J Med Genet. 2011;54:e542–7.

    Article  CAS  Google Scholar 

  10. Tully HM, Ishak GE, Rue TC, Dempsey JC, Browd SR, Millen KJ, et al. Two hundred thirty-six children with developmental hydrocephalus: causes and clinical consequences. J Child Neurol. 2016;31:309–20.

    Article  Google Scholar 

  11. Dong XR, Liu B, Yang L, Wang HJ, Wu BB, Liu RC, 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. 2020;57:558–66.

    Article  CAS  Google Scholar 

  12. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99:877–85.

    Article  CAS  Google Scholar 

  13. Povysil G, Petrovski S, Hostyk J, Aggarwal V, Allen AS, Goldstein DB. Rare-variant collapsing analyses for complex traits: guidelines and applications. Nat Rev Genet. 2019;20:747–59.

    Article  CAS  Google Scholar 

  14. Pinero J, Ramirez-Anguita JM, Sauch-Pitarch J, Ronzano F, Centeno E, Sanz F, et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 2020;48:D845–55.

    CAS  PubMed  Google Scholar 

  15. Harris CA, McAllister JP 2nd. What we should know about the cellular and tissue response causing catheter obstruction in the treatment of hydrocephalus. Neurosurgery. 2012;70:1589–601 (discussion 601–2).

    Article  Google Scholar 

  16. Laeke T, Tirsit A, Biluts H, Murali D, Wester K. Pediatric hydrocephalus in Ethiopia: treatment failures and infections: a hospital-based, retrospective study. World Neurosurg. 2017;100:30–7.

    Article  Google Scholar 

  17. McAllister JP 2nd. Pathophysiology of congenital and neonatal hydrocephalus. Semin Fetal Neonatal Med. 2012;17:285–94.

    Article  Google Scholar 

  18. Ma ML, Wu MX, Li YB, Wu D, Zhang BK. Shunt surgery for early-onset severe hydrocephalus in methylmalonic acidemia: report on two cases and review of the literature. Childs Nerv Syst. 2018;34:1417–21.

    Article  Google Scholar 

  19. Furey CG, Zeng X, Dong W, Jin SC, Choi J, Timberlake AT, et al. Human genetics and molecular mechanisms of congenital hydrocephalus. World Neurosurg. 2018;119:441–3.

    Article  Google Scholar 

  20. Zhang KH, Gao M, Wang GY, Shi YY, Li XY, Lv YQ, et al. Hydrocephalus in cblC type methylmalonic acidemia. Metab Brain Dis. 2019;34:451–8.

    Article  CAS  Google Scholar 

  21. Joseph M, Pai GS, Holden KR, Herman G. X-linked myotubular myopathy: clinical observations in ten additional cases. Am J Med Genet. 1995;59:168–73.

    Article  CAS  Google Scholar 

  22. Kulkarni AV, Riva-Cambrin J, Butler J, Browd SR, Drake JM, Holubkov R, et al. Outcomes of CSF shunting in children: comparison of Hydrocephalus Clinical Research Network cohort with historical controls: clinical article. J Neurosurg Pediatr. 2013;12:334–8.

    Article  Google Scholar 

  23. Ballabh P. Pathogenesis and prevention of intraventricular hemorrhage. Clin Perinatol. 2014;41:47–67.

    Article  Google Scholar 

  24. de Bijl-Marcus KA, Brouwer AJ, de Vries LS, van Wezel-Meijler G. The effect of head positioning and head tilting on the incidence of intraventricular hemorrhage in very preterm infants: a systematic review. Neonatology. 2017;111:267–79.

    Article  Google Scholar 

  25. Wang HQ, Zhao SL, Chen B, Fu CH, Dang YW, Fang PH, et al. Repression of the expression of PPP3CC by ZEB1 confers activation of NF-kappaB and contributes to invasion and growth in glioma cells. Jpn J Clin Oncol. 2018;48:175–83.

    Article  Google Scholar 

  26. Xu XM, Liu W, Cao ZH, Liu MX. Effects of ZEB1 on regulating osteosarcoma cells via NF-kappaB/iNOS. Eur Rev Med Pharmacol Sci. 2017;21:1184–90.

    PubMed  Google Scholar 

  27. Lattke M, Magnutzki A, Walther P, Wirth T, Baumann B. Nuclear factor kappaB activation impairs ependymal ciliogenesis and links neuroinflammation to hydrocephalus formation. J Neurosci. 2012;32:11511–23.

    Article  CAS  Google Scholar 

  28. Singh S, Howell D, Trivedi N, Kessler K, Ong T, Rosmaninho P, et al. Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition. Elife. 2016;5:e12717.

    Article  Google Scholar 

  29. Gavino C, Richard S. Patched1 haploinsufficiency impairs ependymal cilia function of the quaking viable mice, leading to fatal hydrocephalus. Mol Cell Neurosci. 2011;47:100–7.

    Article  CAS  Google Scholar 

  30. Liu CG, Li GR, Wang PP, Wang Y, Pan J. Characterization of spontaneous hydrocephalus development in the young atherosclerosis-prone mice. Neuroreport. 2017;28:1108–14.

    Article  Google Scholar 

  31. Mirzaa G, Parry DA, Fry AE, Giamanco KA, Schwartzentruber J, Vanstone M, et al. De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nat Genet. 2014;46:510–5.

    Article  CAS  Google Scholar 

  32. Long J, Liu Z, Wu XD, Xu YH, Ge CL. siRNA-mediated SBF2 silencing may inhibit pancreatic cancer cells via attenuation of the TGF-beta signaling pathway. Technol Cancer Res Treat. 2016;15:308–13.

    Article  CAS  Google Scholar 

  33. Werry TD, Christopoulos A, Sexton PM. Mechanisms of ERK1/2 regulation by seven-transmembrane-domain receptors. Curr Pharm Des. 2006;12:1683–702.

    Article  CAS  Google Scholar 

  34. Huang X, Fu Y, Charbeneau RA, Neubig RR. GNAI2 and regulators of G protein signaling as a potential Noonan syndrome mechanism. Med Hypotheses. 2009;73:56–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful for the willingness and cooperation of the patients and their families in this study.

Funding

This study was supported by the National Natural Science Foundation of China (81741034), the Shanghai Municipal Commission of Health and Family Planning (GDEK201701), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01 and 2018SHZDZX05), and the Shanghai Shen Kang Hospital Development Center (SHDC12017110).

Author information

Authors and Affiliations

  1. Department of Neonatology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China

    Hong-Fang Mei, Guo-Qiang Cheng, Lai-Shuan Wang, Yun Cao & Wen-Hao Zhou

  2. Key Laboratory of Birth Defects, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China

    Xin-Ran Dong, Yu-Lan Lu, Bing-Bing Wu, Hui-Jun Wang & Wen-Hao Zhou

  3. Center for Molecular Medicine of Children’s Hospital of Fudan University, Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Hui-Yao Chen

  4. Clinical Genetic Center, Children’s Hospital of Fudan University, National Children’s Medical Center, 399 Wan Yuan Road, Shanghai, 201102, China

    Lin Yang & Wen-Hao Zhou

Authors
  1. Hong-Fang Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xin-Ran Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui-Yao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu-Lan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bing-Bing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hui-Jun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guo-Qiang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lai-Shuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yun Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wen-Hao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MHF designed the study, collected data, drafted the initial manuscript, reviewed the manuscript, and revised the manuscript. DXR, CHY, LYL, WBB, and WHJ designed the data collection instruments, performed the initial analyses, and were involved in writing the manuscript. CGQ, WLS, and CY reviewed all cases and were involved with the study design, data analysis, and writing of the manuscript. YL and ZWH were involved with the study design, supervised data collection, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Lin Yang.

Ethics declarations

Ethical approval

This study was approved by the Ethics Committee of the Children’s Hospital of Fudan University, and informed consent was obtained from all the study participants.

Conflict of interest

The authors have no conflict of interest relevant to this article to disclose.

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Table 1 (DOCX 15 KB)

Supplementary Table 2 (DOCX 21 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mei, HF., Dong, XR., Chen, HY. et al. Genetic etiologies associated with infantile hydrocephalus in a Chinese infantile cohort. World J Pediatr 17, 305–316 (2021). https://doi.org/10.1007/s12519-021-00429-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12519-021-00429-w

Keywords

Search

Navigation