Unveiling a Novel THOC2 Mutation's Role in X-linked Intellectual Disability

CASE REPORT
Mehdi Hashemipour, Ayad Neissi, Mostafa Neissi, Misagh Mohammadi-Asl, Motahareh Sheikh-Hosseini, Sasan Bavi, Mojdeh Roghani, Javad Mohammadi-Asl

 
For citation: Hashemipour M, Neissi A, Neissi M, Mohammadi-Asl M, Sheikh-Hosseini M, Bavi S, Roghani M, Mohammadi-Asl J. Unveiling a Novel THOC2 Mutation's Role in X-linked Intellectual Disability. International Journal of Biomedicine. 2024;14(2):352-356. doi:10.21103/Article14(2)_CR5
 
Originally published June 5, 2024
 

Abstract: 

Background: Intellectual disabilities encompass a spectrum of neurodevelopmental disorders profoundly impacting an individual's cognitive abilities, adaptive behaviors, and communication skills. This article delves into the complex challenges encountered by an individual with intellectual disability, particularly examining the interplay between cognitive limitations and speech difficulties, while presenting a case report detailing the experience of a son within a non-consanguineous family diagnosed with intellectual disability due to a new genetic defect in THOC2, thereby contributing significantly to our comprehension of THOC2-related pathogenic variants.
Case presentation: A 14-year-old boy from a non-consanguineous Iranian family presented with significant challenges in academics, communication, and adaptive skills, accompanied by speech problems and exhibiting distinctive physical characteristics. The exome-sequencing analysis revealed a novel hemizygous c.1559+5A>T mutation located in intron 14 (NM_001081550.2) within the THOC2 gene in the proband. Sanger sequencing further confirmed the mother as a carrier of the mutation, although she remains in good health, while the father exhibits a normal genotype. This delineates an X-linked inheritance pattern, shedding light on the familial transmission of the identified genetic anomaly.
Conclusion: The precise identification of the c.1559+5A>T splicing mutation in the THOC2 gene, achieved through exome-sequencing, conclusively diagnoses X-linked intellectual disability in our patient. This breakthrough not only unravels the molecular intricacies contributing to intellectual disability but also underscores the urgency for accurate and swift disease diagnosis.

Keywords: 
intellectual disability • THOC2 gene • mutation • exome-sequencing
References: 
  1. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. (2013). American Psychiatric Publishing, Inc. https://doi.org/10.1176/appi.books.9780890425596
  2. Felce D, Perry J. Quality of life: its definition and measurement. Res Dev Disabil. 1995 Jan-Feb;16(1):51-74. doi: 10.1016/0891-4222(94)00028-8. PMID: 7701092.
  3. Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25. PMID: 28135719; PMCID: PMC6016744.
  4. Kumar R, Corbett MA, van Bon BW, Woenig JA, Weir L, Douglas E et al. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability. Am J Hum Genet. 2015 Aug 6;97(2):302-10. doi: 10.1016/j.ajhg.2015.05.021. Epub 2015 Jul 9. PMID: 26166480; PMCID: PMC4573269.
  5. Strässer K, Masuda S, Mason P, Pfannstiel J, Oppizzi M, Rodriguez-Navarro S et al. TREX is a conserved complex coupling transcription with messenger RNA export. Nature. 2002 May 16;417(6886):304-8. doi: 10.1038/nature746. Epub 2002 Apr 28. PMID: 11979277.
  6. Yamazaki T, Fujiwara N, Yukinaga H, Ebisuya M, Shiki T, Kurihara T et al. The closely related RNA helicases, UAP56 and URH49, preferentially form distinct mRNA export machineries and coordinately regulate mitotic progression. Mol Biol Cell. 2010 Aug 15;21(16):2953-65. doi: 10.1091/mbc.E09-10-0913. Epub 2010 Jun 23. PMID: 20573985; PMCID: PMC2921121.
  7. Accogli A, Scala M, Calcagno A, Castello R, Torella A, Musacchia F et al. Novel CNS malformations and skeletal anomalies in a patient with Beaulieu-boycott-Innes syndrome. Am J Med Genet A. 2018 Dec;176(12):2835-2840. doi: 10.1002/ajmg.a.40534. Epub 2018 Sep 20. PMID: 30238602.
  8. Mattioli F, Isidor B, Abdul-Rahman O, Gunter A, Huang L, Kumar R et al. Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. Hum Mol Genet. 2019 Mar 15;28(6):952-960. doi: 10.1093/hmg/ddy391. PMID: 30476144.
  9. Neissi M, Mohammadi-Asl M, Roghani M, Al-Badran AI, Mohammadi-Asl J. Mutation Detection in MYO15A Gene in an Iranian Family with Non-Syndromic Hearing Loss. Int J Biomed. 2024;14(1):165-169. doi:10.21103/Article14(1)_CR3.
  10. Hashemipour M, Sheikh-Hosseini M, Mabudi H. Association of Autism Spectrum Disorder in an Iranian Pedigree with a Novel Hereditary Mutation in SETD5. Int J Biomed. 2024;14(1):170-174. doi:10.21103/ Article14(1)_CR4.
  11. Neissi M, Mabudi H, Mohammadi-Asl J. AHI1 gene mutation in a consanguineous Iranian family affected by Joubert syndrome: A case report. Clin Case Rep. 2021 Oct 23;9(10):e05002. doi: 10.1002/ccr3.5002. PMID: 34721863; PMCID: PMC8538011.
  12. Neissi M, Al-Badran AI, Mohammadi-Asl J. A Novel Deleterious MYO15A Gene Mutation Causes Nonsyndromic Hearing Loss. Iran J Otorhinolaryngol. 2024 Jan;36(1):355-360. doi: 10.22038/IJORL.2023.69889.3372. PMID: 38259694; PMCID: PMC10800138.
  13. Muthusamy B, Garapati K, Girimaji SC. Exome sequencing identifies a novel mutation in THO complex, subunit 2 in non-syndromic X-linked intellectual disability. Research Reports. 2021(5):e1-e10. doi:10.9777/rr.2021.10002.
  14. Kumar R, Gardner A, Homan CC, Douglas E, Mefford H, Wieczorek D et al. Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery. Hum Mutat. 2018 Aug;39(8):1126-1138. doi: 10.1002/humu.23557. Epub 2018 Jun 14. PMID: 29851191; PMCID: PMC6481655.
  15. Kumar R, Palmer E, Gardner AE, Carroll R, Banka S, Abdelhadi O et al. Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor. Front Mol Neurosci. 2020 Feb 11;13:12. doi: 10.3389/fnmol.2020.00012. PMID: 32116545; PMCID: PMC7026477.

Download Article
Received March 20, 2024.
Accepted May 5, 2024.
©2024 International Medical Research and Development Corporation.