Otizm Olgularında Temel Genetik Testler ve Sendromik Nedenler
Özet
Güncel genomik araştırmalar, otizm spektrum bozukluğunun (OSB) güçlü bir genetik bileşeni olduğunu ve hem kopya sayısı değişiklikleri hem de noktasal varyantlar gibi farklı düzeylerdeki genomik bozuklukların OSB etyolojisine katkıda bulunduğunu göstermektedir. OSB’de genetik nedenler sendromik ve sendromik olmayan biçimlerde ortaya çıkabilir; sendromik olmayan olgularda ise çok sayıda gen ve çevresel faktörün etkileştiği daha karmaşık bir genetik mimari söz konusudur. Klinik değerlendirme, fenotipin dikkatli analizine ek olarak geniş kapsamlı genomik taramaları içerir ve bu yaklaşım hem yüksek etkili varyantları hem de de novo mutasyonları ortaya koyarak tanısal doğruluğu artırır. Modern genomik teknolojiler, OSB'nin altında yatan biyolojik mekanizmaların daha iyi anlaşılmasını sağlamış ve birçok bireyde tanının netleşmesine katkıda bulunmuştur. Bu geniş bakış açısı, OSB'nin genetik yapısının tekil bir nedenden ziyade çok katmanlı ve değişken bir genomik spektrumdan oluştuğunu göstermektedir.
Current genomic research demonstrates that ASD has a strong genetic component, with both copy number changes and single-nucleotide variants contributing to its etiology at multiple genomic levels. Genetic causes in ASD may present as syndromic or non-syndromic, and non-syndromic cases often involve a more complex genetic architecture shaped by the interaction of numerous genes and environmental factors. Clinical evaluation combines detailed phenotypic assessment with broad genomic screening, helping to identify both high-impact variants and de novo mutations, thereby increasing diagnostic yield. Advances in modern genomic technologies have improved our understanding of ASD’s underlying biological mechanisms and have clarified the diagnosis in many individuals. Overall, this broader perspective shows that the genetic basis of ASD is not driven by a single cause but instead reflects a multilayered and variable spectrum of genomic alterations.
Referanslar
Tammimies K, Marshall CR, Walker S, et al. Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. JAMA. 2015;314(9):895-903. doi:10.1001/jama.2015.10078
Wiśniowiecka-Kowalnik B, Nowakowska BA. Genetics and epigenetics of autism spectrum disorder-current evidence in the field. J Appl Genet. 2019;60(1):37-47. doi:10.1007/s13353-018-00480-w
Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15(5):399-407. doi:10.1038/gim.2013.32
Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev. 2012;22(3):229-237. doi:10.1016/j.gde.2012.03.002
Velinov M. Genomic Copy Number Variations in the Autism Clinic-Work in Progress. Front Cell Neurosci. 2019;13:57. Published 2019 Feb 19. doi:10.3389/fncel.2019.00057
Donovan AP, Basson MA. The neuroanatomy of autism - a developmental perspective. J Anat. 2017;230(1):4-15. doi:10.1111/joa.12542
Weiner DJ, Wigdor EM, Ripke S, et al. 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
Acero-Garcés DO, Saldarriaga W, Cabal-Herrera AM, Rojas CA, Hagerman RJ. Fragile X Syndrome in children. Colomb Med (Cali). 2023;54(2):e4005089. Published 2023 May 20. doi:10.25100/cm.v54i2.5089
Hnoonual A, Jankittunpaiboon C, Limprasert P. Screening for FMR1 CGG Repeat Expansion in Thai Patients with Autism Spectrum Disorder. Biomed Res Int. 2021;2021:4359308. Published 2021 Dec 8. doi:10.1155/2021/4359308
Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA. 2004;291(4):460-469. doi:10.1001/jama.291.4.460
Srivastava S, Love-Nichols JA, Dies KA, et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med. 2019;21(11):2413-2421. doi:10.1038/s41436-019-0554-6
Iossifov I, O'Roak BJ, Sanders SJ, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515(7526):216-221. doi:10.1038/nature13908
Sanders SJ, Ercan-Sencicek AG, Hus V, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70(5):863-885. doi:10.1016/j.neuron.2011.05.002
Ruzzo EK, Pérez-Cano L, Jung JY, et al. Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Cell. 2019;178(4):850-866.e26. doi:10.1016/j.cell.2019.07.015
Gigante S, Gouil Q, Lucattini A, et al. Using long-read sequencing to detect imprinted DNA methylation. Nucleic Acids Res. 2019;47(8):e46. doi:10.1093/nar/gkz107
De Coster W, Weissensteiner MH, Sedlazeck FJ. Towards population-scale long-read sequencing. Nat Rev Genet. 2021;22(9):572-587. doi:10.1038/s41576-021-00367-3
Aref-Eshghi E, Kerkhof J, Pedro VP, et al. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders. Am J Hum Genet. 2020;106(3):356-370. doi:10.1016/j.ajhg.2020.01.019)..
Butler, M.; Rafi, S.; Manzardo, A. High-Resolution Chromosome Ideogram Representation of Currently Recognized Genes for Autism Spectrum Disorders. Int. J. Mol. Sci. 2015, 16, 6464–6495.
Varghese, M.; Keshav, N.; Jacot-Descombes, S.; Warda, T.; Wicinski, B.; Dickstein, D.L.; Harony-Nicolas, H.; De Rubeis, S.; Drapeau, E.; Buxbaum, J.D.; et al. Autism Spectrum Disorder: Neuropathology and Animal Models. Acta Neuropathol. 2017, 134, 537–566.
Kotulska, K.; Jóźwiak, S. Autism in Monogenic Disorders. Eur. J. Paediatr. Neurol. 2011, 15, 177–180.
Acero-Garcés, D.O.; Saldarriaga, W.; Cabal-Herrera, A.M.; Rojas, C.A.; Hagerman, R.J. Fragile X Syndrome in Children. Colomb. Med. 2023, 54, e4005089.
Lombardo, B.; Pagani, M.; De Rosa, A.; Nunziato, M.; Migliarini, S.; Garofalo, M.; Terrile, M.; D’Argenio, V.; Galbusera, A.; Nuzzo, T.; et al. D-Aspartate Oxidase Gene Duplication Induces Social Recognition Memory Deficit in Mice and Intellectual Disabilities in Humans. Transl. Psychiatry 2022, 12, 305.
Miles, J.H.; Takahashi, T.N.; Hong, J.; Munden, N.; Flournoy, N.; Braddock, S.R.; Martin, R.A.; Spence, M.A.; Hillman, R.E.; Farmer, J.E. Development and Validation of a Measure of Dysmorphology: Useful for Autism Subgroup Classification. Am. J. Med. Genet. A 2008, 146, 1101–1116.
Vorstman, J.A.S.; Scherer, S.W. Contemplating Syndromic Autism. Genet. Med. 2023, 25, 100919.
Laurvick, C.L.; de Klerk, N.; Bower, C.; Christodoulou, J.; Ravine, D.; Ellaway, C.; Williamson, S.; Leonard, H. Rett Syndrome in Australia: A Review of the Epidemiology. J. Pediatr. 2006, 148, 347–352.
Dimitropoulos, A.; Schultz, R.T. Autistic-like Symptomatology in Prader-Willi Syndrome: A Review of Recent Findings. Curr. Psychiatry Rep. 2007, 9, 159–164.
Moreno-De-Luca, D.; Sanders, S.J.; Willsey, A.J.; Mulle, J.G.; Lowe, J.K.; Geschwind, D.H.; State, M.W.; Martin, C.L.; Ledbetter, D.H. Using Large Clinical Data Sets to Infer Pathogenicity for Rare Copy Number Variants in Autism Cohorts. Mol. Psychiatry 2013, 18, 1090–1095.
Iakoucheva, L.M.; Muotri, A.R.; Sebat, J. Getting to the Cores of Autism. Cell 2019, 178, 1287–1298.
