Sources of Phenotypical Variability in Autism Spectrum Disorder and Their Effects on Treatment

Abstract

Autism Spectrum Disorder (ASD) is a clinically and etiologically heterogeneous neurodevelopmental disorder. Approaching ASD as a single categorical diagnosis without addressing heterogeneity may limit intervention efficacy. A narrative, critical review was conducted using the PubMed database for studies between 2020-2025 and using “autism” AND “heterogeneity” (n= 3869) and “ASD” AND “heterogeneity” (n= 2391). A total of 435 references were selected based on titles, 167 based on abstracts, and 89 based on text reviews. Finally, 59 studies were reviewed. The DSM-5 criteria and their evolution, genetics, gender, environmental/epigenetic risk factors, comorbidities, development, syndromic vs. non-syndromic presentations, simplex vs. multiplex families, and autistic regression were the main sources of heterogeneity in the studies. The “deficit” term in the DSM-5 should be operationalized in conjunction with disability levels. ASD should be better characterized in female samples. Studies on genetic, environmental, and epigenetic risk factors should model these interactions. Protective factors should also be evaluated in future studies. Comorbidities may be grouped according to type (psychiatric vs. medical) and degree (symptom vs. syndrome), and temporal changes in symptoms can be modelled. Incident ASD cases should be screened using genetic tests and evaluated for dysmorphology. International databases of simplex/multiplex families and regressive ASD cases may help better characterize samples.

Keywords

• ASD
• autism
• phenotype
• genetics
• developmental regression
• multiplex

Otı̇zm Spektrum Bozukluğunda Fenotipik Değı̇şkenliğin Kaynakları ve Tedavi Üzerindeki Etkileri

Öz

Otizm Spektrum Bozukluğu (OSB) klinik ve etiyolojik olarak heterojen bir nörogelişimsel bozukluktur. Heterojenliği ele almadan OSB'ye tek bir kategorik tanı olarak yaklaşmak, müdahalelerin etkilerini sınırlayabilir. 2020-2025 yılları arasındaki çalışmalar için PubMed veri tabanı kullanılarak ve “autism” AND “heterogeneity” (n= 3869) ve “autism spectrum disorder” AND “heterogeneity” (n= 2391) kullanılarak anlatısal, eleştirel bir inceleme yapılmıştır. Toplam 435 referans başlıklara göre, 167'si özetlere göre ve 89'u metinler gözden geçirilerek seçilmiştir. Son olarak, 59 çalışma gözden geçirilmiştir. DSM-5 kriterleri ve bunların değişimi, genetik, cinsiyet, çevresel/epigenetik risk faktörleri, komorbiditeler, gelişim, sendromik ve sendromik olmayan sunumlar, simpleks ve multipleks aileler ve otistik regresyon heterojenliğin ana kaynaklarıydı. DSM-5'teki “eksiklik” terimi, engellilik düzeyleri ile birlikte operasyonel hale getirilmelidir. OSB kadın örneklemler arasında daha iyi karakterize edilmelidir. Genetik, çevresel ve epigenetik risk faktörleri üzerine yapılan çalışmalar, bunların etkileşimlerini modellemelidir. Koruyucu faktörler de değerlendirilmelidir. Komorbiditeler türlerine (psikiyatrik ve tıbbi) ve derecelerine (semptom ve sendrom) göre gruplandırılabilir ve semptomlardaki zamansal değişiklikler modellenebilir. OSB vakaları genetik testlerle taranmalı ve dismorfoloji açısından değerlendirilmelidir. Simpleks/ multipleks ailelerin ve gerileyen OSB vakalarının uluslararası veri tabanları, örneklerin daha iyi karakterize edilmesine yardımcı olabilir.

Anahtar Kelimeler

• ASD
• autism
• phenotype
• genetics
• developmental regression
• multiplex

Kaynakça

1. APA (1987) Diagnostic and Statistical Manual of Mental Disorders-Third Edition-Revised (DSM-III-R). Washington DC, American Psychiatric Association.
2. APA (1994) Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV). Washington DC, American Psychiatric Association.
3. APA (2013) Diagnostic and Statistical Manual of Mental Disorders Fifth edition (DSM-5). Washington DC, American Psychiatric Association.
4. Arnett AB, Beighley JS, Kurtz-Nelson EC, Hoekzema K, Wang T, Bernier RA et al. (2020) Developmental predictors of cognitive and adaptive outcomes in genetic subtypes of autism spectrum disorder. Autism Res, 13:1659-1669.
5. Blázquez Hinojosa A, Lázaro Garcia L, Puig Navarro O, Varela Bondelle E, Calvo Escalona R (2021) Sensitivity and specificity of dsm-5 diagnostic criteria for autism spectrum disorder in a child and adolescent sample. Rev Psiquiatr Salud Ment (Engl Ed), 14:202-211.
6. Botelho RM, Silva ALM, Borbely AU (2024) The autism spectrum disorder and ıts possible origins in pregnancy. Int J Environ Res Public Health, 21:244.
7. Bougeard C, Picarel-Blanchot F, Schmid R, Campbell R, Buitelaar J (2024) Prevalence of autism spectrum disorder and co-morbidities in children and adolescents: a systematic literature review. Focus (Am Psychiatr Publ), 22:212-228.
8. Cook J, Hull L, Mandy W (2024) Improving diagnostic procedures in autism for girls and women: a narrative review. Neuropsychiatr Dis Treat, 20:505-514.

9. Cruz S, Zubizarreta SC, Costa AD, Araújo R, Martinho J, Tubío-Fungueiriño M et al. (2024) Is there a bias towards males in the diagnosis of autism? a systematic review and meta-analysis. Neuropsychol Rev. doi:10.1007/s11065-023-09630-2. [In Press]
10. Dougherty JD, Marrus N, Maloney SE, Yip B, Sandin S, Turner TN et al. (2022) Can the "female protective effect" liability threshold model explain sex differences in autism spectrum disorder? Neuron, 110:3243-3262.
11. Dwyer P (2022) The neurodiversity approach(es): what are they and what do they mean for researchers? Hum Dev, 66:73-92.
12. Fang Y, Cui Y, Yin Z, Hou M, Guo P, Wang H et al. (2023) Comprehensive systematic review and meta-analysis of the association between common genetic variants and autism spectrum disorder. Gene, 887:147723.
13. Genovese A, Butler MG (2023) The autism spectrum: behavioral, psychiatric and genetic associations. Genes (Basel), 14:677.
14. Godoy-Giménez M, García-Pérez Á, Cañadas F, Estévez AF, Sayans-Jiménez P (2024) The Broad Autism Phenotype-International Test (BAP-IT): A two-domain-based test for the assessment of the broad autism phenotype. Autism, 28(9), 2362-2380.
15. Happé F, Frith U (2020) Annual research review: looking back to look forward – changes in the concept of autism and implications for future research. J Child Psychol Psychiatry, 61:218–232.
16. Hudac CM, Friedman NR, Ward VR, Estreicher RE, Dorsey GC, Bernier RA et al. (2024) Characterizing sensory phenotypes of subgroups with a known genetic etiology pertaining to diagnoses of autism spectrum disorder and ıntellectual disability. J Autism Dev Disord, 54:2386-2401.
17. Kereszturi É (2023) diversity and classification of genetic variations in autism spectrum disorder. Int J Mol Sci, 24:16768.
18. Lazar SM, Challman TD, Myers SM (2024) Etiologic evaluation of children with autism spectrum disorder. Pediatr Clin North Am, 71:179-197.
19. Leow KQ, Tonta MA, Lu J, Coleman HA, Parkington HC (2024) Towards understanding sex differences in autism spectrum disorders. Brain Res, 1833:148877.
20. Lombardo MV, Mandelli V (2022) Rethinking our concepts and assumptions about autism. Front Psychiatry, 13:903489.
21. Mathew S, Bichenapally S, Khachatryan V, Muazzam A, Hamal C, Velugoti LSDR et al. (2022) Role of serotoninergic antidepressants in the development of autism spectrum disorders: A systematic review. Cureus, 14:e28505.
22. Micai M, Fatta LM, Gila L, Caruso A, Salvitti T, Fulceri F et al. (2023) Prevalence of co-occurring conditions in children and adults with autism spectrum disorder: A systematic review and meta-analysis. Neurosci Biobehav Rev, 155:105436.
23. Mottron L, Bzdok D (2020) Autism spectrum heterogeneity: fact or artifact? Mol Psychiatry, 25:3178-3185.
24. Netto BB, da Silva EP, de Aguiar da Costa M, de Rezende VL, Bolan SJ, Ceretta LB et al. (2024) Critical period of exposure to mercury and the diagnostic of autism spectrum disorder: A systematic review. J Neurochem., 168(9), 2092-2104.
25. Njotto LL, Simin J, Fornes R, Odsbu I, Mussche I, Callens S et al. (2023) maternal and early-life exposure to antibiotics and the risk of autism and attention-deficit hyperactivity disorder in childhood: a swedish population-based cohort study. Drug Saf, 46:467-478.
26. Ochoa-Lubinoff C, Makol BA, Dillon EF (2023) Autism in women. Neurol Clin, 41:381-397.
27. Olusanya BO, Smythe T, Ogbo FA, Nair MKC, Scher M, Davis AC (2023) Global prevalence of developmental disabilities in children and adolescents: A systematic umbrella review. Front Public Health, 11:1122009.
28. Ophir Y, Rosenberg H, Tikochinski R, Dalyot S, Lipshits-Braziler Y (2023) screen time and autism spectrum disorder: a systematic review and meta-analysis. JAMA Netw Open, 6:e2346775.
29. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al. (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 372:n71.
30. Peall KJ, Owen MJ, Hall J (2024) Rare genetic brain disorders with overlapping neurological and psychiatric phenotypes. Nat Rev Neurol, 20:7-21.
31. Pugsley K, Scherer SW, Bellgrove MA, Hawi Z (2022) Environmental exposures associated with elevated risk for autism spectrum disorder may augment the burden of deleterious de novo mutations among probands. Mol Psychiatry, 27:710-730.
32. Roy M, Strate P (2023) autism spectrum disorders in adulthood-symptoms, diagnosis, and treatment. Dtsch Arztebl Int, 120:87-93.
33. Sandin S, Yip BHK, Yin W, Weiss LA, Dougherty JD, Fass S et al. (2024) examining sex differences in autism heritability. JAMA Psychiatry,81(7), 673-680.
34. Suprunowicz M, Tomaszek N, Urbaniak A, Zackiewicz K, Modzelewski S, Waszkiewicz N (2024) Between dysbiosis, maternal ımmune activation and autism: ıs there a common pathway? Nutrients, 16:549.
35. Sukhera J (2022) Narrative reviews: flexible, rigorous, and practical. J Grad Med Educ, 14:414-417.
36. Talantseva OI, Romanova RS, Shurdova EM, Dolgorukova TA, Sologub PS, Titova OS et al. (2023) The global prevalence of autism spectrum disorder: A three-level meta-analysis. Front Psychiatry, 14:1071181.
37. Taylor CM, Finucane BM, Moreno-De-Luca A, Walsh LK, Martin CL, Ledbetter DH (2023) Phenotypic shift in copy number variants: Evidence in 16p11.2 duplication syndrome. Genet Med, 25:151-154.
38. Torres G, Mourad M, Iqbal S, Moses-Fynn E, Pandita A, Siddhartha SS et al. (2023) Conceptualizing epigenetics and the environmental landscape of autism spectrum disorders. Genes (Basel), 14:1734.
39. Wachtel LE, Escher J, Halladay A, Lutz A, Satriale GM, Westover A et al. (2024) Profound autism: An ımperative diagnosis. Pediatr Clin North Am, 71:301-313.
40. Zhao Y, Lu F, Wang X, Luo Y, Zhang R, He P et al. (2024) The economic burden of autism spectrum disorder with and without intellectual disability in China: A nationwide cost-of-illness study. Asian J Psychiatr, 92:103877.
41. Zhuang S, Tan DW, Reddrop S, Dean L, Maybery M, Magiati I (2023) Psychosocial factors associated with camouflaging in autistic people and its relationship with mental health and well-being: A mixed methods systematic review. Clin Psychol Rev, 105:102335.