Otizm Spektrum Bozukluğu Olan Monozigotik İkizlerde Tüm Genom Dizileme Çalışması

Yıl 2022, Cilt: 12 Sayı: 2, 49 - 60, 22.08.2022

Ender Coşkunpınar , Ozlem Bozdagı Gunal

https://doi.org/10.26650/experimed.1067169

Öz

ÖZ
Amaç: Nörogelişimsel bozukluğun en bilinen türü olan Otizm Spektrum Bozukluğu (OSB), bir zihinsel gelişim bozukluğudur. OSB için kesin bir biyobelirteç olmadığından, hastanın davranışının değerlendirilmesine dayalı olarak tanı konmaktadır. OSB'de davranışsal ve sosyal bozuklukların yanı sıra genetik faktörler de önemlidir.
Gereç ve Yöntem: Çalışmada, iki monozigotik ikiz çiftinin (biri uyumsuz diğeri uyumlu) klinik özelliklerinin değerlendirilmesinin yanı sıra, Tüm genom dizileme (WGS) yöntemi ile genetik anormallikler incelenmiştir.
Bulgular: WGS sonuçlarına göre, 29 yeni aday gende 13 yüksek patojenik varyant tespit edilmiştir. Aday genler MEAF6, OR2T8, ABI2, PDE4D, GLIS3, DRD4, LPXN, FAM186A, NEK3, GOLGA8A, SSC5D, ARMCX4, ADAR, LRP1B, DAP, LYRM7, MUC12, CNTNAP3B, TCP11L1, DRD4, ORRC3B ve TCP11L1, ORRC3B’i içermektedir.
Sonuç: OSB'li bireylerde ve ailelerinde hastalığın anlaşılmasında klinik değerlendirmelerin ve genetik değişikliklerin incelenmesinin önemli olduğunu düşünmekteyiz.

Anahtar Kelimeler

Otizm spektrum bozukluğu, MZ ikizler, Tüm genom dizileme (WGS), Genetik

The Study of Whole Genome Sequencing in Monozygotic Twins with Autism Spectrum Disorder

Öz

Objective: Autism spectrum disorder (ASD), the most well-known type of neurodevelopmental disorder, is a mental development disorder. Since there is no definitive biomarker for ASD, diagnosis is made based on the assessment of the patient's behavior. In addition to behavioral and social disorders, genetic factors are also important in ASD.

Materials and Methods: In the study, variant analyses were performed by whole genome sequencing (WGS) method, as well as evaluating the clinical features of two monozygotic twin couples (one discordant and the other concordant).

Results: According to the WGS results, thirteen high pathogenic variants were detected in twenty-nine novel candidate genes. Candidate genes include MEAF6, OR2T8, ABI2, PDE4D, GLIS3, DRD4, LPXN, FAM186A, NEK3, GOLGA8A, SSC5D, ARMCX4, ADAR, LRP1B, DAP, LYRM7, MUC12, CNTNAP3B, TCP11L1, OR8B3, KLRC3, and DPP9.

Conclusion: We speculate that clinical evaluations and examination of genetic changes are important for understanding the disease in individuals with ASD and their families.

Anahtar Kelimeler

Autism spectrum disorder, MZ twins, Whole genome sequencing (WGS), Genetics

Kaynakça

• 1. American Psychiatric Association. Diagnostic and statistical man-ual of mental disorders: DSM-5. Arlington, VA; 2013. google scholar
• 2. Lord C, Brugha TS, Charman T, Cusack J, Dumas G, Frazier T, et al. Autism spectrum disorder. Nat Rev Dis Primers 2020; 6(1): 5. [CrossRef] google scholar
• 3. Maenner MJ, Shaw KA, Baio J, Washington A, Patrick M, DiRienzo M, et al. Prevalence of autism spectrum disorder among children aged 8 years autism and developmental disabilities monitoring network, 11 sites, United States, 2016. MMWR Surveill Summ 2020; 69(4): 1-12. Erratum in: MMWR Morb Mortal Wkly Rep. 2020 Apr 24; 69(16): 503. google scholar
• 4. Tan C, Frewer V, Cox G, Williams K, Ure A. Prevalence and age of onset of regression in children with autism spectrum disorder: A systematic review and meta-analytical update. Autism Res 2021; 14(3): 582-98. [CrossRef] google scholar
• 5. Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J. Autism spectrum disorder. Lancet 2018; 392(10146): 508-20. [CrossRef] google scholar
• 6. Sharma SR, Gonda X, Tarazi FI. Autism Spectrum Disorder: Classifi-cation, diagnosis and therapy. Pharmacol Ther 2018; 190: 91-104. [CrossRef] google scholar
• 7. Tsai CH, Chen KL, Li HJ, Chen KH, Hsu CW, Lu CH, et al. The symp-toms of autism including social communication deficits and repeti-tive and restricted behaviors are associated with different emotion-al and behavioral problems. Sci Rep 2020; 10(1): 20509. [CrossRef] google scholar
• 8. Spence SJ, Sharifi P, Wiznitzer M. Autism spectrum disorder: screening, diagnosis, and medical evaluation. Semin Pediatr Neu-rol 2004; 11(3): 186-95. [CrossRef] google scholar
• 9. Xiao Z, Qiu T, Ke X, Xiao X, Xiao T, Liang F, et al. Autism spectrum disorder as early neurodevelopmental disorder: evidence from the brain imaging abnormalities in 2-3 years old toddlers. J Au-tism Dev Disord 2014; 44(7): 1633-40. [CrossRef] google scholar
• 10. Mannion A, Leader G. Comorbidity in autism spectrum disorder: A literature review. Res Autism Spectr Disord 2013; 7(12): 1595-616. [CrossRef] google scholar
• 11. Holmes H, Sawer F, Clark M. Autism spectrum disorders and epi-lepsy in children: A commentary on the occurrence of autism in epilepsy; how it can present differently and the challenges associ-ated with diagnosis. Epilepsy Behav 2021; 117: 107813. [CrossRef] google scholar
• 12. Imamura A, Morimoto Y, Ono S, Kurotaki N, Kanegae S, Yamamoto N, et al. Genetic and environmental factors of schizophrenia and autism spectrum disorder: insights from twin studies. J Neural Transm (Vienna) 2020; 127(11): 1501-15. [CrossRef] google scholar
• 13. Colvert E, Tick B, McEwen F, Stewart C, Curran SR, Woodhouse E, et al. Heritability of Autism Spectrum Disorder in a UK popu-lation-based twin sample. JAMA Psychiatry 2015; 72(5): 415-23. [CrossRef] google scholar
• 14. Hegarty JP 2nd, Pegoraro LFL, Lazzeroni LC, Raman MM, Hallmay-er JF, Monterrey JC, et al. Genetic and environmental influences on structural brain measures in twins with autism spectrum disor-der. Mol Psychiatry 2020; 25(10): 2556-66. [CrossRef] google scholar
• 15. Taylor MJ, Rosenqvist MA, Larsson H, Gillberg C, D'Onofrio BM, Lichtenstein P, et al. Etiology of Autism Spectrum Disorders and Autistic Traits Over Time. JAMA Psychiatry 2020; 77(9): 936-43. [CrossRef] google scholar
• 16. Wisniowiecka-Kowalnik B, Nowakowska BA. Genetics and epi-genetics of autism spectrum disorder-current evidence in the field. J Appl Genet 2019; 60(1): 37-47. [CrossRef] google scholar
• 17. Ramaswami G, Geschwind DH. Genetics of autism spectrum disor-der. Handb Clin Neurol 2018; 147: 321-9. [CrossRef] google scholar
• 18. Guo H, Peng Y, Hu Z, Li Y, Xun G, Ou J, et al. Genome-wide copy number variation analysis in a Chinese autism spectrum disorder cohort. Sci Rep 2017; 7: 44155. [CrossRef] google scholar
• 19. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014; 515(7526): 209-15. [CrossRef] google scholar
• 20. Harripaul R, Vasli N, Mikhailov A, Rafiq MA, Mittal K, Windpassing-er C, et al. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol Psychiatry 2018; 23(4): 973-84. [CrossRef] google scholar
• 21. Mamoor S. Meaf6 is differentially expressed in the brains of pa-tients with schizophrenia 2020. [CrossRef] google scholar
• 22. Lim ET, Uddin M, De Rubeis S, Chan Y, Kamumbu AS, Zhang X, et al. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat Neurosci 2017; 20(9): 1217-24. Erratum in: Nat Neurosci 2020 Sep; 23(9): 1176. google scholar
• 23. Grady DL, Harxhi A, Smith M, Flodman P, Spence MA, Swanson JM, et al. Sequence variants of the DRD4 gene in autism: further evi-dence that rare DRD4 7R haplotypes are ADHD specific. Am J Med Genet B Neuropsychiatr Genet 2005; 136B(1): 33-5. google scholar
• 24. Ptacek R, Kuzelova H, Stefano GB. Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders. Med Sci Monit 2011; 17(9): RA215-20. google scholar
• 25. Reiersen AM, Todorov AA. Association between DRD4 genotype and Autistic Symptoms in DSM-IV ADHD. J Can Acad Child Ado-lesc Psychiatry 2011; 20(1): 15-21. google scholar
• 26. Gadow KD, DeVincent CJ, Olvet DM, Pisarevskaya V, Hatchwell E. Association of DRD4 polymorphism with severity of oppositional defiant disorder, separation anxiety disorder and repetitive be-haviors in children with autism spectrum disorder. Eur J Neurosci 2010; 32(6): 1058-65. [CrossRef] google scholar
• 27. Gadow KD, DeVincent CJ, Pisarevskaya V, Olvet DM, Xu W, Mendell NR, et al. Parent-child DRD4 genotype as a potential biomarker for oppositional, anxiety, and repetitive behaviors in children with autism spectrum disorder. Prog Neuropsychopharmacol Biol Psy-chiatry 2010; 34(7): 1208-14. [CrossRef] google scholar
• 28. Zamarbide M, Mossa A, Munoz-Llancao P, Wilkinson MK, Pond HL, Oaks AW, et al. Male-Specific cAMP Signaling in the Hippocampus Controls Spatial Memory Deficits in a Mouse Model of Autism and Intellectual Disability. Biol Psychiatry 2019; 85(9): 760-8. [CrossRef] google scholar
• 29. Kaeffer J, Zeder-Lutz G, Simonin F, Lecat S. GPRASP/ARMCX protein family: potential involvement in health and diseases revealed by their novel interacting partners. Curr Top Med Chem 2021; 21(3): 227-54. [CrossRef] google scholar
• 30. Ambalavanan A, Chaumette B, Zhou S, Xie P, He Q, Spiegelman D, et al. Exome sequencing of sporadic childhood-onset schizophrenia suggests the contribution of X-linked genes in males. Am J Med Genet B Neuropsychiatr Genet 2019; 180(6): 335-40. [CrossRef] google scholar
• 31. Tran SS, Jun HI, Bahn JH, Azghadi A, Ramaswami G, Van Nostrand EL, et al. Widespread RNA editing dysregulation in brains from au-tistic individuals. Nat Neurosci 2019; 22(1): 25-36. [CrossRef] google scholar
• 32. Ansell BRE, Thomas SN, Bonelli R, Munro JE, Freytag S, Bahlo M. A survey of RNA editing at single-cell resolution links interneurons to schizophrenia and autism. RNA 2021; 27(12): 1482-96. [CrossRef] google scholar
• 33. Mulatinho MV, de Carvalho Serao CL, Scalco F, Hardekopf D, Pe-kova S, Mrasek K, et al. Severe intellectual disability, omphalocele, hypospadia and high blood pressure associated to a deletion at 2q22.1q22.3: case report. Mol Cytogenet 2012; 5(1): 30. [CrossRef] google scholar
• 34. Carvalho AF, Solmi M, Sanches M, Machado MO, Stubbs B, Ajnaki-na O, et al. Evidence-based umbrella review of 162 peripheral bio-markers for major mental disorders. Transl Psychiatry 2020; 10(1): 152. [CrossRef] google scholar
• 35. Bouchard MF, Chevrier J, Harley KG, Kogut K, Vedar M, Calderon N, et al. Prenatal exposure to organophosphate pesticides and IQ in 7-year-old children. Environ Health Perspect 2011; 119(8): 118995. [CrossRef] google scholar