CNV profiles of Chinese pediatric patients with developmental disorders

Abstract

Purpose

To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders.

Methods

De-identified chromosomal microarray (CMA) data from 10,026 pediatric patients with developmental disorders were collected for re-evaluating the pathogenic CNV (pCNV) yields of different medical conditions and for comparing the frequency and phenotypic variability of genomic disorders between the Chinese and Western patient populations.

Results

The overall yield of pCNVs in the Chinese pediatric patient cohort was 21.37%, with variable yields for different disorders. Yields of pCNVs were positively associated with phenotypic complexity and intellectual disability/developmental delay (ID/DD) comorbidity for most disorders. The genomic burden and pCNV yield in neurodevelopmental disorders supported a female protective effect. However, the stratification analysis revealed that it was seen only in nonsyndromic ID/DD, not in nonsyndromic autism spectrum disorders or seizure. Furthermore, 15 known genomic disorders showed significantly different frequencies in Chinese and Western patient cohorts, and profiles of referred clinical features for 15 known genomic disorders were also significantly different in the two cohorts.

Conclusion

We defined the pCNV yields and profiles of the Chinese pediatric patients with different medical conditions and uncovered differences in the frequency and phenotypic diversity of genomic disorders between Chinese and Western patients.

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Fig. 1: The sex bias in copy-number variant (CNV) burden for patients with neurodevelopmental disorders (NDDs).
Fig. 2: Frequencies and clinical features of genomic disorders between Chinese and Western patient cohorts.
Fig. 3: Novel neurodevelopmental disorder (NDD)-related genomic disorders using de novo evidence from independent patients.

Data availability

The CNV data sets used for the study are available from the corresponding author upon request.

References

  1. 1.

    Lee, C., Iafrate, A. J. & Brothman, A. R. Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat. Genet. 39(7 Suppl), S48–S54 (2007).

    CAS  Article  Google Scholar 

  2. 2.

    Itsara, A. et al. Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet. 84, 148–161 (2009).

    CAS  Article  Google Scholar 

  3. 3.

    Miller, D. T. et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J. Hum. Genet. 86, 749–764 (2010).

    CAS  Article  Google Scholar 

  4. 4.

    Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science. 316, 445–449 (2007).

    CAS  Article  Google Scholar 

  5. 5.

    McTague, A., Howell, K. B., Cross, J. H., Kurian, M. A. & Scheffer, I. E. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 15, 304–316 (2015).

    Article  Google Scholar 

  6. 6.

    Cooper, G. M. et al. A copy number variation morbidity map of developmental delay. Nat. Genet. 43, 838–846 (2011).

    CAS  Article  Google Scholar 

  7. 7.

    Shen, Y. et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics. 125, e727–e735 (2010).

    Article  Google Scholar 

  8. 8.

    Coe, B. P. et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat. Genet. 46, 1063–1071 (2014).

    CAS  Article  Google Scholar 

  9. 9.

    Kaminsky, E. B. et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet. Med. 13, 777–784 (2011).

    Article  Google Scholar 

  10. 10.

    Firth, H. V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84, 524–533 (2009).

    CAS  Article  Google Scholar 

  11. 11.

    Fan, Y. et al. Chromosomal microarray analysis in developmental delay and intellectual disability with comorbid conditions. BMC Med. Genomics 11, 49 (2018).

    Article  Google Scholar 

  12. 12.

    Wang, R. et al. Application of chromosome microarray analysis in patients with unexplained developmental delay/intellectual disability in South China. Pediatr. Neonatol. 60, 35–42 (2019).

    Article  Google Scholar 

  13. 13.

    Cheng, S. S. W. et al. Experience of chromosomal microarray applied in prenatal and postnatal settings in Hong Kong. Am. J. Med. Genet. C Semin. Med. Genet. 181, 196–207 (2019).

    PubMed  Google Scholar 

  14. 14.

    Geng, J. et al. Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield. BMC Genomics 15, 1127 (2014).

    Article  Google Scholar 

  15. 15.

    Zhang, C. et al. CNVbase: batch identification of novel and rare copy number variations based on multi-ethnic population data. J. Genet. Genomics 44, 367–370 (2017).

    Article  Google Scholar 

  16. 16.

    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).

    Article  Google Scholar 

  17. 17.

    Girirajan, S. et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N. Engl. J. Med. 367, 1321–1331 (2012).

    CAS  Article  Google Scholar 

  18. 18.

    Ruderfer, D. M. et al. Patterns of genic intolerance of rare copy number variation in 59,898 human exomes. Nat. Genet. 48, 1107–1111 (2016).

    CAS  Article  Google Scholar 

  19. 19.

    Jacquemont, S. et al. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am. J. Hum. Genet. 94, 415–425 (2014).

    CAS  Article  Google Scholar 

  20. 20.

    Ikeshima, H., Imai, S., Shimoda, K., Hata, J. & Takano, T. Expression of a MADS box gene, MEF2D, in neurons of the mouse central nervous system: implication of its binary function in myogenic and neurogenic cell lineages. Neurosci. Lett. 200, 117–120 (1995).

    CAS  Article  Google Scholar 

  21. 21.

    Yang, Q. et al. Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science. 323, 124–127 (2009).

    CAS  Article  Google Scholar 

  22. 22.

    Le Meur, N. et al. MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J. Med. Genet. 47, 22–29 (2010).

    Article  Google Scholar 

  23. 23.

    Demeer, B. et al. Duplication 16p13.3 and the CREBBP gene: confirmation of the phenotype. Eur. J. Med. Genet. 56, 26–31 (2013).

    Article  Google Scholar 

  24. 24.

    Thienpont, B. et al. Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. J. Med. Genet. 47, 155–161 (2010).

    CAS  Article  Google Scholar 

  25. 25.

    Jordan, T. et al. The human PAX6 gene is mutated in two patients with aniridia. Nat. Genet. 1, 328–332 (1992).

    CAS  Article  Google Scholar 

  26. 26.

    Davis, L. K. et al. Pax6 3’ deletion results in aniridia, autism and mental retardation. Hum. Genet. 123, 371–378 (2008).

    CAS  Article  Google Scholar 

  27. 27.

    Aalfs, C. M. et al. Tandem duplication of 11p12-p13 in a child with borderline development delay and eye abnormalities: dose effect of the PAX6 gene product? Am. J. Med. Genet. 73, 267–271 (1997).

    CAS  Article  Google Scholar 

  28. 28.

    Aradhya, S., Smaoui, N., Marble, M. & Lacassie, Y. De novo duplication 11p13 involving the PAX6 gene in a patient with neonatal seizures, hypotonia, microcephaly, developmental disability and minor ocular manifestations. Am. J. Med. Genet. A. 155A, 442–444 (2011).

    Article  Google Scholar 

  29. 29.

    Guo, H. et al. Genome-wide copy number variation analysis in a Chinese autism spectrum disorder cohort. Sci. Rep. 7, 44155 (2017).

    Article  Google Scholar 

  30. 30.

    Hu, G. et al. Copy number variations in 119 Chinese children with idiopathic short stature identified by the custom genome-wide microarray. Mol. Cytogenet. 9, 16 (2016).

    Article  Google Scholar 

  31. 31.

    Truty, R. et al. Prevalence and properties of intragenic copy-number variation in Mendelian disease genes. Genet. Med. 21, 114–123 (2019).

    CAS  Article  Google Scholar 

  32. 32.

    Park, K. B. et al. Effects of copy number variations on developmental aspects of children with delayed development. Ann. Rehabil. Med. 43, 215–223 (2019).

    Article  Google Scholar 

  33. 33.

    Li, J., Oehlert, J., Snyder, M., Stevenson, D. K. & Shaw, G. M. Fetal de novo mutations and preterm birth. PLoS Genet. 13, e1006689 (2017).

    Article  Google Scholar 

  34. 34.

    Zaidi, S. & Brueckner, M. Genetics and genomics of congenital heart disease. Circ. Res. 120, 923–940 (2017).

    CAS  Article  Google Scholar 

  35. 35.

    Catusi, I. et al. Testing single/combined clinical categories on 5110 Italian patients with developmental phenotypes to improve array-based detection rate. Mol. Genet. Genomic Med. 8, e1056 (2019).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Mullen, S. A. et al. Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology. 81, 1507–1514 (2013).

    Article  Google Scholar 

  37. 37.

    Coe, B. P. et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat. Genet. 51, 106–116 (2018).

    Article  Google Scholar 

  38. 38.

    Levy, D. et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron. 70, 886–897 (2011).

    CAS  Article  Google Scholar 

  39. 39.

    Koolen, D. A. et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38, 999–1001 (2006).

    CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by grants from CAMS Innovation Fund for Medical Sciences (2016‐I2M‐1‐008), the Beijing Natural Science Foundation (7202019 to X. Chen), the Chinese National Nature Science Fund (31671310 to X. Chen, 81873633 to Y.S.), the Eastern Scholar Fund, the Guangxi Bagui Scholar Fund, National Key Research and Development Program (2018YFC1002501), the Major Research Plan of the Provincial Science and Technology Foundation of Guangxi (AB16380214) to Y.S., Capital Health Research and Development of Special (2020-1-4071 and 2020-2-1131), and the Innovation Project of Beijing Municipal Human Resources and Social Security Bureau to X. Chen. The authors thank all involved families who contributed their de-identified CMA data to research, and are particularly grateful for the subset who collaborated on follow-up, providing detailed clinical information. The authors thank members of the collaborating clinical laboratories for performing the microarray experiments.

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Authors

Contributions

Conceptualization: Y.S., X.Chen. Writing: Y.S., X.Chen, H.Y., J.F.G. Review and editing: Y.S., X.Chen, J.F.G. CMA data and collection: H.Y., S.S., J.L., J.S., R.Y., Shun Zhang. CNV curation and first-round pathogenic interpretation: J.L., S.S., R.Y. CNV second-round pathogenic interpretation H.Y., J.W., X.Chen, and Y.S. Data statistics analysis: Z.L. Western CNV literature review, the comparison between Chinese and Western cohorts for CNV frequency and referred phenotype: S.S., Z.L., H.Y. Clinical information collection: H.Y., Q.C., Z.G., Y.Zhu, X.W., L.Liu, J.Z., H.Li, H.Q., Y.Lin, H.Z., M.Y., M.M., L.Z., D.Z., H.W., H.Lv, Y.Liu, and L.Liang. CMA testing and validation: S.S., J.S., C.L., Shujie Zhang, W.Li, W.Lu, Y.Zhang, H.X., F.L., Q.W., B.X., C.G. Resources and software support and intelligent suggestion: Y.Liu and X.Cui.

Corresponding authors

Correspondence to Yiping Shen or Xiaoli Chen.

Ethics declarations

Ethics Declaration

The study was approved by the ethics committee of the respective institutions (Capital Institute of Pediatrics, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region), which allowed us to perform aggregate analysis using de-identified clinical CMA data. Additional informed consents were obtained from the parents of some individuals to publish their detailed clinical information.

Competing interests

The authors declare no competing interests.

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Yuan, H., Shangguan, S., Li, Z. et al. CNV profiles of Chinese pediatric patients with developmental disorders. Genet Med (2021). https://doi.org/10.1038/s41436-020-01048-y

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