Skip to main content
SpringerLink
Log in

Detection of copy number variants and genes by chromosomal microarray in an Emirati neurodevelopmental disorders cohort

  • Original Article
  • Published:
neurogenetics Aims and scope Submit manuscript

Abstract

Copy number variations (CNVs) are highly implicated in the etiology of neurodevelopmental disorders (NDDs), and chromosomal microarray analysis (CMA) has been recommended as a first-tier test for many NDDs. We undertook a study to identify clinically relevant CNVs and genes in an ethnically homogenous population of the United Arab Emirates. We genotyped 98 patients with NDDs using genome-wide chromosomal microarray analysis, and observed 47.1% deletion and 52.9% duplication CNVs, of which 11.8% are pathogenic, 23.5% are likely pathogenic, and 64.7% VOUS. The average size of copy number losses (3.9 Mb) was generally higher than of gains (738.4 kb). Analysis of VOUS CNVs for constrained genes (enrichment for brain critical exons and high pLI genes) yielded 7 unique genes. Among these 7 constrained genes, we propose FNTA and PXK as potential candidate genes for neurodevelopmental disorders, which warrants further investigation. Thirty-two overlapping CNVs (Decipher and ClinVar) containing the FNTA gene were previously identified in NDD patients and 6 overlapping CNVs (Decipher and ClinVar) containing the PXK gene were previously identified in NDD patients. Our study supports the utility of CMA for CNV profiling which aids in precise genetic diagnosis and its integration into therapeutics and management of NDD patients.

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
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

All data are presented in the manuscript and supplementary information.

Code availability

NA.

References

  1. Hansen BH, Oerbeck B, Skirbekk B, Petrovski BE, Kristensen H (2018) Neurodevelopmental disorders: prevalence and comorbidity in children referred to mental health services. Nord J Psychiatry 72(4):285–291. https://doi.org/10.1080/08039488.2018.1444087

    Article  PubMed  Google Scholar 

  2. Parenti I, Rabaneda LG, Schoen H, Novarino G (2020) Neurodevelopmental disorders: from genetics to functional pathways. Trends Neurosci 43(8):608–621. https://doi.org/10.1016/j.tins.2020.05.004

    Article  CAS  PubMed  Google Scholar 

  3. Gilissen C et al (2014) Genome sequencing identifies major causes of severe intellectual disability. Nature 511(7509):344–347. https://doi.org/10.1038/nature13394

    Article  CAS  PubMed  Google Scholar 

  4. First MB (2013) Diagnostic and statistical manual of mental disorders, 5th edition, and clinical utility. J Nerv Ment Dis 201(9):727–9. https://doi.org/10.1097/NMD.0b013e3182a2168a

    Article  PubMed  Google Scholar 

  5. M. Woodbury-Smith et al. (2017) Variable phenotype expression in a family segregating microdeletions of the NRXN1 and MBD5 autism spectrum disorder susceptibility genes. NPJ Genom Med. 2. https://doi.org/10.1038/s41525-017-0020-9

  6. Woodbury-Smith M et al (2017) Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly. Mol Autism 8:59. https://doi.org/10.1186/s13229-017-0175-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. M. Woodbury-Smith et al (2022) Mutational landscape of autism spectrum disorder brain tissue. Genes. 13 (2);207 [Online]. Available: https://www.mdpi.com/2073-4425/13/2/207

  8. Girirajan S, Campbell CD, Eichler EE (2011) Human copy number variation and complex genetic disease. Annu Rev Genet 45:203–226. https://doi.org/10.1146/annurev-genet-102209-163544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jang W et al (2019) Chromosomal microarray analysis as a first-tier clinical diagnostic test in patients with developmental delay/intellectual disability, autism spectrum disorders, and multiple congenital anomalies: a prospective multicenter study in Korea. Ann Lab Med 39(3):299–310. https://doi.org/10.3343/alm.2019.39.3.299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tammimies K et al (2015) Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA 314(9):895–903. https://doi.org/10.1001/jama.2015.10078

    Article  CAS  PubMed  Google Scholar 

  11. al-Gazali LI, Bener A, Abdulrazzaq YM, Micallef R, al-Khayat AI, Gaber T (1997) Consanguineous marriages in the United Arab Emirates. J Biosoc Sci. 29(4):491–7. https://doi.org/10.1017/s0021932097004914

    Article  CAS  PubMed  Google Scholar 

  12. Akter H et al (2021) Whole exome sequencing uncovered highly penetrant recessive mutations for a spectrum of rare genetic pediatric diseases in Bangladesh. NPJ Genom Med. 6(1):14. https://doi.org/10.1038/s41525-021-00173-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Richards S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  14. Subramanian A et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545–15550. https://doi.org/10.1073/pnas.0506580102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Uddin M et al (2014) Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat Genet 46(7):742–747. https://doi.org/10.1038/ng.2980

    Article  CAS  PubMed  Google Scholar 

  16. Lek M et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291. https://doi.org/10.1038/nature19057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sunkin SM et al (2013) Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system. Nucleic Acids Res 41(Database issue):D996–D1008. https://doi.org/10.1093/nar/gks1042

    Article  CAS  PubMed  Google Scholar 

  18. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B (2008) Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 5(7):621–628. https://doi.org/10.1038/nmeth.1226

    Article  CAS  PubMed  Google Scholar 

  19. Nassir N et al (2021) Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells. Hum Genomics 15(1):68. https://doi.org/10.1186/s40246-021-00368-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cao J et al (2020) A human cell atlas of fetal gene expression. Science. 370 (6518). https://doi.org/10.1126/science.aba7721

  21. Szklarczyk D et al (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43(Database issue):D447-52. https://doi.org/10.1093/nar/gku1003

    Article  CAS  PubMed  Google Scholar 

  22. Pinner AL, Mueller TM, Alganem K, McCullumsmith R, Meador-Woodruff JH (2020) Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex. Transl Psychiatry 10(1):3. https://doi.org/10.1038/s41398-019-0610-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ruderfer DM et al (2016) Patterns of genic intolerance of rare copy number variation in 59,898 human exomes. Nat Genet 48(10):1107–1111. https://doi.org/10.1038/ng.3638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jones KL et al (2017) Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation. Mol Psychiatry 22(2):273–279. https://doi.org/10.1038/mp.2016.77

    Article  CAS  PubMed  Google Scholar 

  25. Szczaluba K et al (2018) Neurodevelopmental phenotype caused by a de novo PTPN4 single nucleotide variant disrupting protein localization in neuronal dendritic spines. Clin Genet 94(6):581–585. https://doi.org/10.1111/cge.13450

    Article  CAS  PubMed  Google Scholar 

  26. Bitetto G, Di Fonzo A (2020) Nucleo-cytoplasmic transport defects and protein aggregates in neurodegeneration. Transl Neurodegener 9(1):25. https://doi.org/10.1186/s40035-020-00205-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nguyen JM, Qualmann KJ, Okashah R, Reilly A, Alexeyev MF, Campbell DJ (2015) 5p deletions: current knowledge and future directions. Am J Med Genet C Semin Med Genet 169(3):224–238. https://doi.org/10.1002/ajmg.c.31444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Phelan MC (2008) Deletion 22q13.3 syndrome. Orphanet J Rare Dis 3:14. https://doi.org/10.1186/1750-1172-3-14

    Article  PubMed  PubMed Central  Google Scholar 

  29. Phelan K, McDermid HE (2012) The 22q13.3 deletion syndrome (Phelan-McDermid syndrome). Mol Syndromol 2(3–5):186–201. https://doi.org/10.1159/000334260

    Article  CAS  PubMed  Google Scholar 

  30. Bacchelli E et al (2015) Analysis of CHRNA7 rare variants in autism spectrum disorder susceptibility. Am J Med Genet A 167A(4):715–723. https://doi.org/10.1002/ajmg.a.36847

    Article  CAS  PubMed  Google Scholar 

  31. Uhlen M et al (2010) Towards a knowledge-based Human Protein Atlas. Nat Biotechnol 28(12):1248–1250. https://doi.org/10.1038/nbt1210-1248

    Article  CAS  PubMed  Google Scholar 

  32. Li H et al (2016) Protein prenylation constitutes an endogenous brake on axonal growth. Cell Rep 16(2):545–558. https://doi.org/10.1016/j.celrep.2016.06.013

    Article  CAS  PubMed  Google Scholar 

  33. Lin Z, Li J, Ji T, Wu Y, Gao K, Jiang Y (2021) ATP1A1 de novo mutation-related disorders: clinical and genetic features. Front Pediatr 9:657256. https://doi.org/10.3389/fped.2021.657256

    Article  PubMed  PubMed Central  Google Scholar 

  34. Guillen Sacoto MJ et al (2020) De novo variants in the ATPase module of MORC2 cause a neurodevelopmental disorder with growth retardation and variable craniofacial dysmorphism. Am J Hum Genet 107(2):352–363. https://doi.org/10.1016/j.ajhg.2020.06.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are thankful to all patients and their families for participating in the study. We thank Emile Myron D Verano for the assistance in data compilation.

Funding

This research was funded by including College of Medicine at Mohammed Bin Rashid University of Medicine and Health Sciences, grant number MBRU-CM-RG2018-04 and MBRU-CM-RG2020-12, Sandooq Al Watan grant (SWARD-F2018-002), and Al Jalila Foundation. Dr. Nasna Nassir was supported by the MBRU Post-Doctoral Fellow Award (MBRU-PD-2020–02).

Author information

Authors and Affiliations

  1. College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates

    Nasna Nassir, Shaiban Al Shaibani, Awab Ahmed, Ahmad Abou Tayoun, Mohammed Uddin & Ammar Albanna

  2. Mental Health Center of Excellence, Al Jalila Children’s Hospital, Dubai, United Arab Emirates

    Isra Sati & Ammar Albanna

  3. Brain Research Institute, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Subang Jaya, Malaysia

    Isra Sati

  4. Nuffield Department of Surgical Science, University of Oxford, Oxford, UK

    Omar Almidani

  5. Genetics and Genomic Medicine Centre, NeuroGen Children’s Healthcare, Dhaka, Bangladesh

    Hosneara Akter

  6. Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK

    Marc Woodbury-Smith

  7. Al Jalila Genomics Center, Al Jalila Children’s Hospital, Dubai, United Arab Emirates

    Ahmad Abou Tayoun

  8. Cellular Intelligence (Ci) Lab, GenomeArc Inc., Toronto, ON, Canada

    Mohammed Uddin

Authors
  1. Nasna Nassir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isra Sati
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shaiban Al Shaibani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Awab Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Omar Almidani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hosneara Akter
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marc Woodbury-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ahmad Abou Tayoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mohammed Uddin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ammar Albanna
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: N.N., M.U., and A.A.B.; methodology: N.N., I.S., S.A.S., and A.A.B.; software: N.N., H.A., and A.A; formal analysis: N.N., M.U., A.A.B., I.S., S.A.S., O.A., H.A., M.W.S., A.A.T.; data curation: N.N., I.S., O.A.; writing—original draft preparation: N.N., M.U., A.A.B., M.W.S., I.S.; writing—review and editing: N.N., M.U., A.A.B., M.W.S., A.A.T.

Corresponding authors

Correspondence to Mohammed Uddin or Ammar Albanna.

Ethics declarations

Ethics approval

This study (AJCH-37) was approved by Dubai Health Authority (DHCA).

Consent to participate

No consent was sought from participants given that the study involved only a de-identified retrospective review of patient data.

Consent for publication

NA

Conflict of interest

The authors declare no competing interests.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nassir, N., Sati, I., Al Shaibani, S. et al. Detection of copy number variants and genes by chromosomal microarray in an Emirati neurodevelopmental disorders cohort. Neurogenetics 23, 137–149 (2022). https://doi.org/10.1007/s10048-022-00689-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-022-00689-2

Keywords

Search

Navigation