NOVEL HOMOZYGOUS VARIANT OF TBC1D8 GENE IN FOUR LIBYAN SIBLINGS WITH AUTISTIC SPECTRUM DISORDER AND INTELLECTUAL DISABILITY WITHOUT EPILEPSY

AUTISTIC SPECTRUM DISORDER

Authors

  • Adel Zeglam Tripoli University Hospital
  • Dr. Al-Khadra General Hospital

Keywords:

TBC1D8,Autism spectrum disorder ,Libya, intellectual disability

Abstract

A global prevalence of Autistic Spectrum Disorder (ASD) was estimated on review of epidemiological studies and has been found to be increasing. Recent progress in genetic analysis and investigations has enabled researchers to identify potential genetic changes that may play a role in ASD. TBC1D8 (TBC1 Domain Family Member 8) is a Protein Coding gene. Among its related pathways is cell cycle. The number of genes connected with autism is growing. Whole exome sequencing (WES) identified the homozygous TBC1D8 variant.

The aim of this article is to report for the first time a TBC1D8 missense variant (c.1883G>A, p. (Arg628Gln) in 4 Libyan children (3 homozygous,1 heterozygous) with severe neurodevelopmental phenotypes (ASD) and intellectual disability(ID). Based on the data of HGMD and ClinVar, variants in only a few autosomal recessive intellectual disability (ARID) genes seem to be reported frequently. None of the large (ARID) studies that were accomplished on over 100 families showed any particularly common gene in (ARID). Molecular genetic analysis of (WES) was carried out on blood samples from these children. The outcome of the genetic investigations was interpreted within the context of clinical finding, family history, and suspected mode of inheritance. The number of genes associated with autism is increasing. WES identified the TBC1D8 variant. According to the longest isoform (NM_001102426.1), the nomenclature of this variant is c.1883G>A, p. (Arg628Gln) in TBC1D8 which leads to an amino acid exchange. This variant has not previously reported or described in the literature (PubMed, HGMD).In this case report we have provided evidence for a connection between TBC1D8 variant and ASD and ID; however, this evidence should be considered preliminary in the context of a single case report and such findings need to be replicated to gain insight in order to determine if ASD and ID are a characteristic of this variant.

Author Biography

Dr., Al-Khadra General Hospital

Pediatric Specialist

Al-Khadra General Hospital

Tripoli, Libya

References

1. van Bokhoven H .(2011) Genetic and epigenetic networks in intellectual disabilities. Annu Rev Genet 45: 81–104. https://doi.org/10.1146/annurev-genet-110410-132512
2. McCarthy S, Gillis J, Kramer M et al.(2014) De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Mol Psychiatry 19 652–658. https://doi.org/10.1038/mp.2014.29
3. De Rubeis S, He X, Goldberg A et al.(2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515 209–215.
. https://doi.org/10.1038/nature13772
4. Mabb AM, Ehlers MD .(2010) Ubiquitination in postsynaptic function and plasticity. Annu Rev Cell Dev Biol 26: 179–210.
https://doi.org/10.1146/annurev-cellbio-100109-104129
5. Hegde, AN, Upadhya SC. (2011). Role of ubiquitin-proteasome-mediated proteolysis in nervous system disease. Biochimica et biophysica acta, 1809(2), 128–140. https://doi.org/10.1016/j.bbagrm.2010.07.006
6. Riazuddin S, Hussain M, Razzaq A, Iqbal Z, Shahzad M, Polla DL, Song Y, van Beusekom E, Khan A, Tomas-Roca L et al. (2016) Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Mol Psychiatry. https://doi.org/10.1038/mp.2016.109
7. AAIDD (American Association on Intellectual Developmental Disabilities). (2010). Intellectual disability: Definition, classification, and systems of supports. Washington, DC: AAIDD.
8. APA (American Psychiatric Association). (2013). Diagnostic and statistical manual of mental disorders. Fifth ed. Washington, DC: APA; 2013.
9. Sztainberg Y, Zoghbi H. (2016) Lessons learned from studying syndromic autism spectrum disorders. Nat Neurosci 19, 1408–1417
https://doi.org/10.1038/nn.4420
10. CDC, National Center for Health Statistics.(2015) Estimated Prevalence of Autism and Other Developmental Disabilities Following Questionnaire Changes in the 2014 National Health Interview Survey, Number 87, November 13. http://www.cdc.gov/nchs/products/nhsr.htm.
11. Zeglam AM, Maouna A.(2012) Is there a need for a focused health care service for children with autistic spectrum disorders? A keyhole look at this problem in Tripoli, Libya. Autism 16:337–9 https://doi.org/10.1177/1362361310393535
12. Zeglam AM, Maouna AJ.(2012) Prevalence of autistic spectrum disorders in Tripoli, Libya: the need for more research and planned services. East Mediterr Health J 18(2): 184-188. https://apps.who.int/iris/handle/10665/118465
13. Zeglam AM.; Al-Bloushi H. (2012) Autism today in Libya: Is it a tip of an iceberg? A comparative study. World Family Medicine Journal. Vol. 10 (8): p34-38.
14. Richards S, Aziz N, Bale 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
15. Emery AEH. Rimoin DL, editor. (2007) Emery and Rimoin’s principles and practice of medical genetics. Churchill Livingstone Elsevier.
16. Moeschler JB, Shevell M. (2006). American Academy of Pediatrics Committee on G. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics; 117(6):2304–16; www.pediatrics.org/cgi/doi/10.1542/
peds.2006-1006 [PubMed: 16740881].
17. Sparrow SS, Cicchetti DV, Saulnier CA (2016). Vineland-3: Vineland Adaptive Behavior Scales. 3rd ed. Pearson Assessments; Minneapolis, MN, USA. [Google Scholar]
18. Autism Speaks.(2016) Modified checklist for autism in toddlers, revised (M-CHAT-R). Retrieved from
http://www.autismspeaks.org/what-autism/diagnosis/screen-your-child
19. Conners CK. (1997) Conners’ Rating Scales-Revised Technical Manual. North Tonawanda, NY: Multi Health Systems; Google Scholar.
20. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, Rubis SD, Collins R et al.(2020) “Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism”. Cell , Volume 180, Issue3, P568-584.E23
https://doi.org/10.1016/j.cell.2019.12.036
21. Dong C, Wei P, Jian X, Gibb R, Boerwinkle, E., Wang, K., & Liu, X. (2015). Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Human molecular genetics, 24(8): 2125–2137.
https://doi.org/10.1093/hmg/ddu733
22. Riazuddin S, Hussain M, Razzaq A, Iqbal Z, Shahzad M, Polla DL, et al. (2018).Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Mol Psychiatry; 22:1604–14. https://doi.org/10.1038/mp.2016.109
23. Baxter, A., Brugha, T., Erskine, H., Scheurer, R., Vos, T., & Scott, J. (2015). The epidemiology and global burden of autism spectrum disorders. Psychological Medicine, 45(3), 601-613. https://doi.org/10.1017/S003329171400172X
24. Wright CF, Fitzpatrick DR, Firth HV. (2018). Pediatric genomics: diagnosing rare disease in children. Nat Rev Genet. ; 19:253–268. https://doi.org/10.1038/nrg.2017.116
25. Bult CJ, Blake JA, Smith CL, Kadin JA, Richardson JE, the Mouse Genome Database Group. (2019). Mouse Genome Database (MGD). Nucleic Acids Res. 2019 Jan. 8; 47 (D1): D801–D806. https://doi.org/10.1093/nar/gky1056
26. Smith, C. M., Hayamizu, T. F., Finger, J. H., Bello, S. M., McCright, I. J., Xu, J., Baldarelli, R. M., Beal, J. S., Campbell, J., Corbani, L. E., Frost, P. J., Lewis, J. R., Giannatto, S. C., Miers, D., Shaw, D. R., Kadin, J. A., Richardson, J. E., Smith, C. L., & Ringwald, M. (2019). The mouse Gene Expression Database (GXD): 2019 update. Nucleic acids research, 47(D1), D774–D779. https://doi.org/10.1093/nar/gky922
27. Epi25 Collaborative, (2019); Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals: Am. J. Hum. Genet., 105 (2), pp. 267-282, https://doi.org/10.1016/j.ajhg.2019.05.

Published

07-10-2021

How to Cite

Zeglam, A., & Alhmadi, S. (2021). NOVEL HOMOZYGOUS VARIANT OF TBC1D8 GENE IN FOUR LIBYAN SIBLINGS WITH AUTISTIC SPECTRUM DISORDER AND INTELLECTUAL DISABILITY WITHOUT EPILEPSY: AUTISTIC SPECTRUM DISORDER. Innovare Journal of Medical Sciences, 9(6). Retrieved from https://innovareacademics.in/journals/index.php/ijms/article/view/41029

Issue

Section

Case Study(s) / Case Report (s)