Формирование когнитивных процессов у детей с аутизмом. Часть II. Генетические механизмы

Аутизм и расстройства аутистического спектра — нервно-психические заболевания, которые начинают проявляться у детей в возрасте до 3 лет. За последнее десятилетие число детей с расстройствами аутистического спектра увеличилось в 10 раз и продолжает расти, составляя 1–2% населения планеты. В настоящее время диагностика расстройств аутистического спектра основывается только на клинических и поведенческих тестах, а биологические и генетические маркеры, которые могли бы способствовать раннему выявлению этого расстройства, отсутствуют. Цель: на основе анализа современных данных литературы о симптомах, генетических этиологических факторах, ассоциированных с аутизмом, изучить возмож- ность использования генов в качестве диагностических биомаркеров у детей с расстройствами аутистического спектра. Анализ данных литературы свидетельствует, что в основе нарушений внимания, скорости обработки информации, рабочей памяти, обучения лежат генетические (патогенные варианты, SNP) изменения экспрессии многих генов: BDNF, CAPS2, CNTNAP2, GABRB3, FMR1, FOXP1, GTF2I, HSD11B2, MECP2, NF2, NGF, NR3C1, OXTR, PAK2, RELN, SLC6A4, UBE3A и др. Некоторые из этих генов (RELN) ассоциированы с тяжестью расстройств аутистического спектра.

1. Jasoliya M., Gu J., AlOlaby R.R., Durbin-Johnson B., Chedin F., Tassone F. Profiling Genome-Wide DNA Methylation in Children with Autism Spectrum Disorder and in Children with Fragile X Syndrome. Genes (Basel) 2022; 13(10): 1795. DOI: 10.3390/genes13101795

2. Autism spectrum disorders. World Health Organization. http://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disorders / Ссылка активна на 6.02.2024.

3. Maenner M.J., Shaw K.A., Baio J. 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: 1. DOI: 10.15585/mmwr.ss6802a1

4. Living With Autism. https://www.easterseals.com/in-sw/explore-resources/living-with-autism / Ссылка активна на 03.10.2023.

5. Cortese S., Solmi M., Michelini G., Bellato A., Blanner C., Canozzi A. et al. Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: A systematic review. World Psychiatry 2023; 22: 129–149. DOI: 10.1002/wps.21037

6. Doernberg E., Hollander E. Neurodevelopmental disorders (ASD and ADHD): DSM-5, ICD-10, and ICD-11. CNS Spectrums 2016; 21(4): 295–299. DOI: 10.1017/S1092852916000262

7. Treffert D.A. The savant syndrome: an extraordinary condition. A synopsis: past, present, future. Philosophical Transactions of The Royal Society B. Biol Scie 2009; 364(1522): 1351–1357. DOI: 10.1098/rstb.2008.0326

8. Lai M.C., Lombardo M.V., Baron-Cohen S. Autism. Lancet 2014; 383(9920): 896–910. DOI: 10.1016/S0140–6736(13)61539–1

9. Kaufmann W.E., Kidd S. A., Andrews H.F., Budimirovic D.B., Esler A., Haas-Givler B. et al. Autism Spectrum Disorder in Fragile X Syndrome: Cooccurring Conditions and Current Treatment. Pediatrics 2017; 139(Suppl 3): S194–S206. DOI: 10.1542/peds.2016–1159F

10. Buiting K., Williams C., Horsthemke B. Angelman syndrome — insights into a rare neurogenetic disorder. Nat Rev Neurol 2016; 12(10): 584–593. DOI: 10.1038/nrneurol.2016.133

11. Horigane S.-I., Ozawa Y., Zhang J., Todoroki H., Miao P., Haijima A. et al. A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development. FEBS Open Bio 2020; 10(8): 1436–1446. DOI: 10.1002/2211–5463.12924

12. Spinazzi N.A., Velasco A.B., Wodecki D.J., Patel L. Autism Spectrum Disorder in Down Syndrome: Experiences from Caregivers. J Autism Dev Disord 2023. DOI: 10.1007/s10803–022–05758-x

13. Quesnel-Vallières M., Weatheritt R.J., Cordes S.P., Blencowe B.J. Autism Spectrum Disorder: Insights into Convergent Mechanisms from Transcriptomics. Nat Rev Genet 2019; 20: 51–63. DOI: 10.1038/s41576–018–0066–2

14. Dickerson A.S., Rahbar M.H., Bakian A.V., Bilder D.A., Harrington R.A., Pettygrove S. et al. Autism spectrum disorder prevalence and associations with air concentrations of lead, mercury, and arsenic. Environment Monitoring Assessm 2016; 188(7): 407. DOI: 10.1007/s10661–016–5405–1

15. Bölte S., Girdler S., Marschik P.B. The contribution of environmental exposure to the etiology of autism spectrum disorder. Cell Mol Life Sci 2019; 76: 1275–1297. DOI: 10.1007/s00018–018–2988–4

16. Emberti Gialloreti L., Mazzone L., Benvenuto A., Fasano A., Alcon A.G., Kraneveld A. et al. Risk and protective environmental factors associated with autism spectrum disorder: evidence-based principles and recommendations. J Clin Med 2019; 8(2): 217. DOI: 10.3390/jcm8020217

17. Cheroni C., Caporale N., Testa G. Autism spectrum disorder at the crossroad between genes and environment: Contributions; convergences; and interactions in ASD developmental pathophysiology. Mol Autism 2020; 11: 69. DOI: 10.1186/s13229–020–00370–1

18. Falk A., Heine V.M., Harwood A.J., Sullivan P.F., Peitz M., Brüstle O. et al. Modeling psychiatric disorders: from genomic findings to cellular phenotypes. Mol Psychiatry 2016; 21(9): 1167–1179. DOI: 10.1038/mp.2016.89

19. De Rubeis S., He X., Goldberg A.P., Poultney C.S., Samocha K., Cicek A.E. et al. Synaptic, Transcriptional and Chromatin Genes Disrupted in Autism. Nature 2014; 515: 209–215. DOI: 10.1038/nature13772

20. Gaugler T., Klei L., Sanders S.J., Bodea C.A., Goldberg A.P., Lee A.B. et al. Most Genetic Risk for Autism Resides with Common Variation. Nat Genet 2014; 46: 881–885. DOI: 10.1038/ng.3039

21. Sanders S.J., He X., Willsey A.J., Ercan-Sencicek A.G., Samocha K.E., Cicek A.E. et al. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron 2015; 87: 1215–1233. DOI: 10.1016/j.neuron.2015.09.016

22. Yu T.W., Chahrour M.H., Coulter M.E., Jiralerspong S., Okamura-Ikeda K., Ataman B. et al. Using Whole-Exome Sequencing to Identify Inherited Causes of Autism. Neuron 2013; 77: 259–273. DOI: 10.1016/j.neuron.2012.11.002

23. Doan R.N., Lim E.T., De Rubeis S., Betancur C., Cutler D.J., Chiocchetti A.G., et al.; Autism Sequencing Consortium. Recessive Gene Disruptions in Autism Spectrum Disorder. Nat Genet 2019; 51: 1092–1098. DOI: 10.1038/s41588–019–0433–8

24. Yang C., Li J., Wu Q., Yang X., Huang A.Y., Zhang J. et al. AutismKB 2.0: A knowledgebase for the genetic evidence of autism spectrum disorder. Database 2018; 2018: bay106. DOI: 10.1093/database/bay106

25. Weiner D.J., Wigdor E.M., Ripke S., Walters R.K., Kosmicki J.A., Grove J., et al.; iPSYCH-Broad Autism Group. Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat Genet 2017; 49(7): 978–985. DOI: 10.1038/ng.3863

26. Lord C., Brugha T.S., Charman T., Cusack J., Dumas G., Frazier T. et al. Autism spectrum disorder. Nat Rev Dis Prim 2020; 6: 5. DOI: 10.1038/s41572–019–0138–4

27. Lozano R., Gbekie C., Siper P.M., Srivastava S., Saland J.M., Sethuram S. et al. FOXP1 Syndrome: A Review of the Literature and Practice Parameters for Medical Assessment and Monitoring. J Neurodev Disord 2021; 13(1): 18. DOI: 10.1186/s11689–021–09358–1

28. Lavado A., He Y., Paré J., Neale G., Olson E.N., Giovannini M., Cao X. Tumor Suppressor Nf2 Limits Expansion of the Neural Progenitor Pool by Inhibiting Yap/Taz Transcriptional Coactivators. Development 2013; 140: 3323–3334. DOI: 10.1242/dev.096537

29. Antonell A., Del Campo M., Magano L.F., Kaufmann L., de la Iglesia J.M., Gallastegui F. et al. Partial 7q11.23 Deletions Further Implicate GTF2I and GTF2IRD1 as the Main Genes Responsible for the Williams-Beuren Syndrome Neurocognitive Profile. J Med Genet 2010; 47(5): 312–320. DOI: 10.1136/jmg.2009.071712

30. Wang Y., Zeng C., Li J., Zhou Z., Ju X., Xia S. et al. PAK2 Haploinsufficiency Results in Synaptic Cytoskeleton Impairment and Autism-Related Behavior. Cell Rep 2018; 24: 2029–2041. DOI: 10.1016/j.celrep.2018.07.061

31. Noroozi R., Taheri M., Ghafouri-Fard S., Bidel Z., Omrani M. D., Moghaddam A.S. et al. Meta-analysis of GABRB3 Gene Polymorphisms and Susceptibility to Autism Spectrum Disorder. J Mol Neurosci 2018; 65(4): 432–437. DOI: 10.1007/s12031–018–1114–2

32. Provenzi L., Fumagalli M., Sirgiovanni I., Giorda, R., Pozzoli U., Morandi F. et al. Pain-related stress during the Neonatal Intensive Care Unit stay and SLC6A4 methylation in very preterm infants. Front Behavioral Neuroscie 2015; 9: 99. DOI: 10.3389/fnbeh.2015.00099

33. Kertes D.A., Kamin H.S., Hughes D.A., Rodney N.C., Bhatt S., Mulligan C.J. Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic–Pituitary–Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo. Child Dev 2016; 87: 61–72. DOI: 10.1111/cdev.12487

34. Jensen Peña C., Monk C., Champagne F.A. Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain. PloS One 2012; 7(6): e39791. DOI: 10.1371/journal.pone.0039791

35. Pierzynowska K., Gaffke L., Żabińska M., Cyske Z., Rintz E., Wiśniewska K. et al. Roles of the Oxytocin Receptor (OXTR) in Human Diseases. Intern J Mol Sci 2023; 24(4): 3887. DOI: 10.3390/ijms24043887

36. Song X., Zhou X., Yang F., Liang H., Wang Z., Li R. et al. Association between prenatal bisphenol a exposure and promoter hypermethylation of CAPS2, TNFRSF25, and HKR1 genes in cord blood. Environ Res 2020; 190: 109996. DOI: 10.1016/j.envres.2020.109996

37. Kundakovic M., Jaric I. The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders. Genes (Basel) 2017; 8(3): 104. DOI: 10.3390/genes8030104

38. Aloe L., Rocco M.L., Bianchi P., Manni L. Nerve growth factor: from the early discoveries to the potential clinical use. J Transl Med 2012; 10: 239. DOI: 10.1186/1479–5876–10–239

39. Poot M. Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders. Mol Syndromol 2015; 6(1): 7–22. DOI: 10.1159/000371594

40. Jossin Y. Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation. Biomolecules 2020; 10: 964. DOI: 10.3390/biom10060964

41. Davis J.K., Broadie K. Multifarious Functions of the Fragile X Mental Retardation Protein. Trends Genet 2017; 33(10): 703–714. DOI: 10.1016/j.tig.2017.07.008

42. Sánchez-Lafuente C.L., Kalynchuk L.E., Caruncho H.J., Ausió J. The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression. Cells 2022; 11(4): 748. DOI: 10.3390/cells11040748

43. Greer P.L., Hanayama R., Bloodgood B.L., Mardinly A.R., Lipton D.M., Flavell S.W. et al. The Angelman Syndrome-associated ubiquitin ligase Ube3A regulates synapse development by ubiquitinating Arc. Cell 2010; 140(5): 704–716. DOI: 10.1016/j.cell.2010.01.026

44. Chen M., Sun Y., Qian Y., Chen N., Li H., Wang L., Dong M. Case report: FOXP1 syndrome caused by a de novo splicing variant (c.1652+5 G>A) of the FOXP1 gene. Front Genet 2022; 13: 926070. DOI: 10.3389/fgene.2022.926070

45. Chen X., Wang M., Zhang Q., Hou Y., Huang X., Li S., Wu J. Stress response genes associated with attention deficit hyperactivity disorder: A case-control study in Chinese children. Behav Brain Res 2019; 363: 126–134. DOI: 10.1016/j.bbr.2019.01.051

46. Wu S., Jia M., Ruan Y., Liu J., Guo Y., Shuang M. et al. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry 2005; 58: 74–77. DOI: 10.1016/j.biopsych.2005.03.013

47. Liu X., Kawamura Y., Shimada T., Otowa T., Koishi S., Sugiyama T. et al. Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population. J Hum Genet 2010; 55: 137–141. DOI: 10.1038/jhg.2009.140

48. Lerer E., Levi S., Salomon S., Darvasi A., Yirmiya N., Ebstein R.P. Association between the oxytocin receptor (OXTR) gene and autism: Relationship to Vineland Adaptive Behavior Scales and cognition. Mol Psychiatry 2008; 13: 980–988. DOI: 10.1038/sj.mp.4002087

49. LoParo D., Waldman I.D. The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis. Mol Psychiatry 2015; 20: 640–646. DOI: 10.1038/mp.2014.77

50. Ocakoğlu F.T., Köse S., Özbaran B., Onay H. The oxytocin receptor gene polymorphism -rs237902- is associated with the severity of autism spectrum disorder: A pilot study. Asian J Psychiatr 2018; 31: 142–149. DOI: 10.1016/j.ajp.2018.01.002

51. Yoo H.J., Yang S.Y., Cho I.H., Park M., Kim S.A. Polymorphisms of BDNF Gene and Autism Spectrum Disorders: Family Based Association Study with Korean Trios. Psychiatry Investig 2014; 11(3): 319–324. DOI: 10.4306/pi.2014.11.3.319

52. Li D., Zhang L., Bai T., Huang W., Ji G-J., Yang T. et al. Common variants of the autism-associated CNTNAP2 gene contribute to the modulatory effect of social function mediated by temporal cortex. Behav Brain Res 2021; 409:113319. DOI: 10.1016/j.bbr.2021.113319

53. Wen Z., Cheng T-L., Li G-Z., Sun S-B., Yu S-Y., Zhang Y. et al. Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation. Mol Autism 2017; 8: 43. DOI: 10.1186/s13229–017–0157–5

54. Xing L., Simon J.M., Ptacek T.S., Yi J.J., Loo L., Mao H. et al. Autism-linked UBE3A gain-of-function mutation causes interneuron and behavioral phenotypes when inherited maternally or paternally in mice. Cell Rep 2023; 42(7): 112706. DOI: 10.1016/j.celrep.2023.112706

55. Moore L., Le T., Fan G. DNA Methylation and Its Basic Function. Neuropsychopharmacol 2013; 38: 23–38. DOI: 10.1038/npp.2012.112