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Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy

Nature Medicine (2024)Cite this article

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Abstract

Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys. Utilizing the current gold standard in genetic diagnostics, 387 of these 1,578 children (24.5%) received genetic diagnoses. We identified 412 pathogenic and likely pathogenic (P/LP) variants across 219 genes associated with neurodevelopmental disorders, and 59 P/LP copy number variants. The genetic diagnostic rate of children with CP labeled at birth with perinatal asphyxia was higher than the rate in children without asphyxia (P = 0.0033). Also, 33 children with CP manifestations (8.5%, 33 of 387) had findings that were clinically actionable. These results highlight the need for early genetic testing in children with CP, especially those with risk factors like perinatal asphyxia, to enable evidence-based medical decision-making.

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Fig. 1: Flowchart of the CP cohort.
Fig. 2: Overview of P/LP variants identified in known neurodevelopmental-related genes.
Fig. 3: ES revealed CP risk factors with biological significance.
Fig. 4: Discovery of candidate genes through large case–control association analysis of CP.

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Data availability

The sequencing data from our patients have been deposited securely in the Genome Sequence Archive (GSA) housed within the National Genomics Data Center at the China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences. The raw sequencing data are available under restricted access in GSA-Human (BioProject accession no.: PRJCA023830 (https://ngdc.cncb.ac.cn/gsa-human/)) due to patient privacy and Regulations on the Management of Human Genetics Resources of China, following the GSA guidelines (https://ngdc.cncb.ac.cn/gsa-human/document). VCF files of 1,578 children with clinical manifestations of CP have been deposited in the National Human Genetic Resources system (Record no.: *BF2023081113944). For access to data, please email qhxing@fudan.edu.cn or changlian.zhu@neuro.gu.se. The committee reviews data access requests on a monthly basis. This statement pertains to the distribution of sequencing data produced by our research. In addition, the P/LP/VUS variants within our CP cohort and previously reported P/LP/VUS variants in other CP cohorts are accessible at http://81.70.179.157/ all the time. The databases used in our analysis are all publicly available and can be obtained from the following links: ClinVar: https://www.ncbi.nlm.nih.gov/clinvar; Gene Ontology: http://geneontology.org; gnomAD: http://www.gnomad-sg.org; and Kyoto Encyclopedia of Genes and Genomes (KEGG): https://www.genome.jp/kegg.

Code availability

All codes used in this manuscript have been deposited and are publicly available at https://github.com/YeCheng57/CerebralPalsy_pipeline.

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Acknowledgements

We thank B. Han and X. Chen from the Institute of Pediatrics, Children’s Hospital of Fudan University for their help with the nematode Caenorhabditis elegans experiment, and Y. Ping from the Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University for his help in the fly Drosophila melanogaster experiment. We also thank the Core Facility of Shanghai Medical College, Fudan University for use of instruments. This work was supported by the Shanghai Municipal Commission of Science and Technology Research Project (19JC1411000 to Q.X.), the National Natural Science Foundation of China (U21A20347 to C. Zhu; 31972880, 32170615 and 31371274 to Q.X. and 82203969 to X.W.), the National Key Research and Development Program from the Ministry of Science and Technology of the People’s Republic of China (2021YFC2700800 to Q.X. and 2022YFC2704800 to C. Zhu), the National Key Research and Development Plan for Stem Cell and Translational Research (2017YFA0104202 to Q.X.), the collaborative innovation center project construction for Shanghai Women and Children’s Health (to Q.X.), a grant from Department of Science and Technology of Henan Province for international collaboration (GZS2023003 to X.W.), the Health Department of Henan Province (SBGJ202301009 to C. Zhu), Swedish governmental grants to scientists working in healthcare (ALFGBG-965197 to C. Zhu, ALFGBG-966034 to X.W.), the Swedish Research Council (2018-02267 and 2022-01019 to C. Zhu, and 2015-06276 and 2021-01950 to X.W.) and the Brain Foundation (FO2022-0120 to C. Zhu).

Author information

Author notes

  1. These authors contributed equally: Yangong Wang, Yiran Xu, Chongchen Zhou, Ye Cheng.

Authors and Affiliations

  1. Children’s Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China

    Yangong Wang, Ye Cheng, Yimeng Qiao, Yangyi Fan, Jin Zhang, Yu Su, Qiaoli Li, Lei Liu & Qinghe Xing

  2. Department of Pediatrics, Henan Key Laboratory of Child Brain Injury and Henan Pediatric Clinical Research Center, The Third Affiliated Hospital and Institute of Neuroscience of Zhengzhou University, Zhengzhou, China

    Yiran Xu, Lei Xia, Juan Song, Yimeng Qiao, Xiaoli Zhang, Ming Li, Xirui Peng, Bingbing Li, Yanyan Sun, Bohao Zhang, Tongchuan Li, Hongwei Li, Junying Yuan, Dengna Zhu & Changlian Zhu

  3. Rehabilitation Department, Henan Key Laboratory of Child Genetics and Metabolism, Children’s Hospital of Zhengzhou University, Zhengzhou, China

    Chongchen Zhou, Qing Shang, Chao Gao, Caiyun Ma & Nan Lv

  4. Shanghai Center for Women and Children’s Health, Shanghai, China

    Ye Cheng, Jin Zhang & Qinghe Xing

  5. State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine (Shanghai), and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China

    Niu Qiao

  6. Department of Neurosurgery, The Affiliated Zhongshan Hospital of Fudan University, Shanghai, China

    Silin Wu

  7. Department of Radiology, Neuroradiology Section, Kingston Health Sciences Centre, Queen’s University Faculty of Health Sciences, Kingston, Ontario, Canada

    Andres Moreno-De-Luca

  8. Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia

    Alastair H. MacLennan & Jozef Gecz

  9. Centre for Perinatal Medicine and Health, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Xiaoyang Wang

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Contributions

Q.X., C. Zhu and X.W. were responsible for study conception, design, supervision and funding as well as analysis and interpretation of the data. Y.W., Y.C. and N.Q. were responsible for performing the ES, data acquisition, analysis and interpretation. Y.X., C. Zhou, Q.S., L.X., J.S., C.G., M.L. and D.Z. were responsible for cohort ascertainment, recruitment and phenotypic characterization. Y.W. drafted the manuscript and Q.X., C. Zhu, X.W., A.H.M., A.M.-D.-L. and J.G. revised the manuscript critically for important intellectual content. N.Q., Y.Q., X.Z., C.M., Y.F., X.P., S.W., N.L., B.L., Y. Sun, B.Z., T.L., H.L., J.Z., Y. Su, Q.L., J.Y., L.L. and D.Z. provided data, developed models, reviewed results and provided guidance on methods. All authors contributed and critically reviewed the final version of the manuscript.

Corresponding authors

Correspondence to Changlian Zhu or Qinghe Xing.

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Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks David Amor, David Ledbetter and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Sonia Muliyil, in collaboration with the Nature Medicine team.

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

Extended data

Extended Data Fig. 1 The correlation between CP phenotypes and genetic findings.

In order to determine the relationship between the different clinical phenotypes and the molecular diagnosis of individuals with CP, we performed clinical grouping of individuals, including classification, developmental profiles, and morphological examination. Global developmental delay/Intellectual Disability(GDD/ID), termed intellectual disability, was identified based on a score of less than 70 on the Bayley scales for measurement of the mental development index. The classification of CP shown in a includes groups with a large number of individuals: spastic quadriplegia, spastic diplegia, dyskinesia CP, and mixed types. The developmental profiles shown in b show complications of individuals with CP, such as speech disability. Shown in c are some imaging findings of CP, such as white matter injury and hydrocephalus. The results show that children with GDD/ID were closely related to heredity. The green is genetic diagnosis positive rate, and the gray is genetic diagnosis negative rate. The numbers on the top of the column represent the corresponding number of people. A two-side Fisher’s exact test was used in comparison of genetic diagnostic rate in specific CP subgroup. Bonferroni was used to handle multiple test problem. ‘*’ means P < 0.05, ‘**’ means P < 0.01, and ‘***’ means P < 0.001.

Extended Data Fig. 2 Phenotype detection of nematode motility development.

After the strains L4440 and Escherichia coli containing target gene RNAi were fed to rrf-3 mutant nematode and TU3311 strain, we measured and analyzed the body length, body width, moving distance and speed. The differences were compared using a statistical method called the Log-rank(Mantel-Cox) Test. n = 50 worms for each case. ‘*’ means P < 0.05, ‘**’ means P < 0.01, and ‘***’ means P < 0.001. Data are presented as mean values +/− SEM. a. Mean Worm Length (um): The body length showed no significant difference in nmpg-1 or tom-1 target gene RNAi bacteria feeding rrf-3 mutant nematode (P = 0.22 and 0.075, respectively), but the body length was increased when feeding TU3311 strain nematode (P = 0.044 and 0.0011 in TU3311). b. Mean Width (um): There was no significant difference in the body width of the mutant strains (P = 0.53 and 0.18 in rrf-3, and P = 0.72 and 0.10 in TU3311). c. Speed (um/s): When the tom-1 target gene RNAi bacteria were fed to rrf-3 mutant nematode, the movement speed was significantly slower than that of the nematode fed by L4440 bacteria (P = 0.0002). When feeding tom-1 target gene RNAi bacteria to TU3311 strain nematode, the movement speed was faster than that fed by L4440 strain nematode (P = 0.011). For nmgp-1 RNAi bacteria fed rrf-3 mutant nematode and TU3311 strain nematode, there was no significant difference (P = 0.88 and 0.21, respectively). d. Track Length (um): When feeding tom-1 target gene RNAi bacteria to rrf-3 nematode, the distance was shorter than that fed by L4440 bacteria (P = 0.0002). When feeding tom-1 target gene RNAi bacteria to TU3311 strain nematode, the track length was longer than that fed by L4440 strain nematode (P = 0.011). There was no significant difference in distance when feeding nmgp-1 target gene RNAi bacteria (P = 0.88 and 0.21 in rrf-3 and TU3311 strain, respectively).

Extended Data Fig. 3 Knockdown of Tom and Bsg affects larval and adult locomotion.

a. Relative crawling speed of a single 3rd instar larval was measured as the number of squares (sqr) crossed during test for each genotype as indicated (P = 0.019 and 0.0002 for Bsg knockdown). n = 15 larvae for each case. b. Adult climbing locomotion was measured as the time for 50% flies to reach the threshold line (8 cm from the bottom) for different genotypes as indicated (P = 0.0062 and 0.0010 for Tom knockdown; P = 0.0022 and 0.0043 for Bsg knockdown). n = 6 flies for each case. The differences were compared using a statistical method called the Log-rank (Mantel-Cox) Test. ‘*’ means P < 0.05, ‘**’ means P < 0.01, and ‘***’ means P < 0.001. Data are presented as mean values +/− SEM.

Extended Data Fig. 4 Filtering process for annotated files.

The screening procedure according to the ACMG for (likely) pathogenic variants through annotated files is shown for a single sample. After deletion of some sites like high-frequency sites and synonymous sites, the preliminary analysis of the sites was performed through prediction software scoring. The remaining variants were further divided into categories based on the literature. All variants were verified by Sanger sequencing.

Extended Data Fig. 5 The KEGG pathway of the P/LP-variants-related genes and VUS-related genes.

a showed the KEGG pathway using P/ LP-variants-related genes (n = 218). And b is the KEGG pathway using VUS-related genes (n = 299). The size of the circle represents the number of genes in the pathway. Hypergeometric test was used in the pathway enrichment analysis and Benjamin and Hochberg method was applied to deal with the multiple correction problem. The color is the corrected p-value, and the darker the color, the more significant the p-value.

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Wang, Y., Xu, Y., Zhou, C. et al. Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy. Nat Med (2024). https://doi.org/10.1038/s41591-024-02912-z

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