NOVEL HOMOZYGOUS VARIANT OF TBC1 DOMAIN FAMILY MEMBER 8 GENE IN FOUR LIBYAN SIBLINGS WITH AUTISTIC SPECTRUM DISORDER AND INTELLECTUAL DISABILITY WITHOUT EPILEPSY

ADEL ZEGLAM; SUAD ALHMADI

doi:10.22159/ijms.2021.v9i6.41029

Authors

ADEL ZEGLAM Department of Pediatrics, Faculty of Medicine, Tripoli University Hospital, Tripoli, Libya.
SUAD ALHMADI Department of Paediatrics, Al-Khadra General Hospital, Tripoli, Libya.

DOI:

https://doi.org/10.22159/ijms.2021.v9i6.41029

Keywords:

TBC1D8, Autism, Libya, Epilepsy

Abstract

Objective: Recent progress in genetic analysis and investigations have enabled researchers to identify potential genetic changes that may play a role in ASD. The number of genes connected with autism is growing. Whole exome sequencing(WES) identified the homozygous TBC1D8 variant. Aim 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.

Method: 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.

Results: 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).

Conclusion: 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

SUAD ALHMADI, Department of Paediatrics, Al-Khadra General Hospital, Tripoli, Libya.

Pediatric Specialist

Al-Khadra General Hospital

Tripoli, Libya

References

van Bokhoven H. Genetic and epigenetic networks in intellectual

disabilities. Annu Rev Genet 2011;45:81-104.

McCarthy S, Gillis J, Kramer M, Lihm J, Yoon S, Berstein Y, et al.

De novo mutations in schizophrenia implicate chromatin remodeling

and support a genetic overlap with autism and intellectual disability.

Mol Psychiatry 2014;19:652-8.

de Rubeis S, He X, Goldberg A, Poultney CS, Samocha K, Cicek AE,

et al. Synaptic, transcriptional and chromatin genes disrupted in autism.

Nature 2014;515:209-15.

Mabb AM, Ehlers MD. Ubiquitination in postsynaptic function and

plasticity. Annu Rev Cell Dev Biol 2010;26:179-210.

Hegde AN, Upadhya SC. Role of ubiquitin-proteasome-mediated

proteolysis in nervous system disease. Biochim Biophys Acta

;1809:128-40.

Riazuddin S, Hussain M, Razzaq A, Iqbal Z, Shahzad M, Polla DL,

et al. Exome sequencing of Pakistani consanguineous families

identifies 30 novel candidate genes for recessive intellectual disability.

Mol Psychiatry 2017;22:1604-14.

AAIDD (American Association on Intellectual Developmental

Disabilities). Intellectual Disability: Definition, Classification, and

Systems of Supports. Washington, DC: AAIDD; 2010.

APA (American Psychiatric Association). Diagnostic and Statistical

Manual of Mental Disorders. 5th ed. Washington, DC: APA; 2013.

Sztainberg Y, Zoghbi H. Lessons learned from studying syndromic

autism spectrum disorders. Nat Neurosci 2016;19:1408-17.

CDC, National Center for Health Statistics. Estimated Prevalence of

Autism and Other Developmental Disabilities Following Questionnaire

Changes in the 2014 National Health Interview Survey, No. 87; 2015.

Available from: http://www.cdc.gov/nchs/products/nhsr.htm

Zeglam AM, Maouna A. 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 2012;16:337-9.

Zeglam AM, Maouna AJ. Prevalence of autistic spectrum disorders in Tripoli, Libya: The need for more research and planned services. East Mediterr Health J 2012;18:184-8.

Zeglam AM, Al-Bloushi H. Autism today in Libya: Is it a tip of an iceberg? A comparative study. World Fam Med J 2012;10:34-8.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. 2015;17:405-24.

Emery AEH, Rimoin DL, editors. Emery and Rimoin’s Principles and Practice of Medical Genetics. London, United Kingdom: Churchill Livingstone, Elsevier; 2007.

Moeschler JB, Shevell M, American Academy of Pediatrics Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics 2006;117:2304-16.

Sparrow SS, Cicchetti DV, Saulnier CA. Vineland-3: Vineland Adaptive Behavior Scales. 3rd ed. Minneapolis, MN, USA: Pearson Assessments; 2016.

Autism Speaks. Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R); 2016. Available from: http://www.autismspeaks.org/ what-autism/diagnosis/screen-your-child

Conners CK. Conners’ Rating Scales-Revised Technical Manual. North Tonawanda. New York: Multi Health Systems; 1997.

Satterstrom FK, Kosmicki JA, Wang J, Breen MS, Rubis SD, Collins R, et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 2020;180:568-84.e23.

Dong C, Wei P, Jian X, Gibb R, Boerwinkle E, Wang K, et al. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet 2015;24:2125-37.

Baxter AJ, Brugha TS, Erskine HE, Scheurer RW, Vos T, Scott JG. The epidemiology and global burden of autism spectrum disorders. Psychol Med 2015;45:601-13.

Wright CF, Fitzpatrick DR, Firth HV. Paediatric genomics: Diagnosing rare disease in children. Nat Rev Genet 2018;19:253-68.

Bult CJ, Blake JA, Smith CL, Kadin JA, Richardson JE, The Mouse Genome Database Group. Mouse genome database (MGD) 2019. Nucleic Acids Res 2019;47:D801-6.

Smith CM, Hayamizu TF, Finger JH, Bello SM, McCright IJ, Xu J, et al. The mouse gene expression database (GXD): 2019 Update. Nucleic Acids Res 2019;47:D774-9.

Epi25 Collaborative. Ultra-rare genetic variation in the epilepsies: A whole-exome sequencing study of 17, 606 individuals. Am J Hum Genet 2019;105:267-82.