¹Undergraduate Medical Student (MBBS), ICARE Institute of Medical Sciences and Research and Dr. Bidhan Chandra Roy Hospital, Haldia, West Bengal, India
²Associate Professor, Department of Medical Physiology, ICARE Institute of Medical Sciences and Research and Dr. Bidhan Chandra Roy Hospital, Haldia, West Bengal, India
³Clinical Psychologist, Pavlov Research Institute and Hospital, Kolkata, West Bengal, India

*Corresponding Author: Sukanti Bhattacharyya, Associate Professor, Department of Medical Physiology, ICARE Institute of Medical Sciences and Research and Dr. Bidhan Chandra Roy Hospital, Haldia, West Bengal, India.

Received: December 31, 2021; Published: February 14, 2022

Abstract

Autism is a neurodevelopmental disorder first introduced by Kanner in 1943. Presently, a group of disorders collectively is considered to be ‘Autism Spectrum Disorder’ which is an outcome of complex interaction between genes and the environment. In this investigation, authors considered the historical development of genetic study that revealed the secret of genes responsible for autism. They noted that synapse-related risk genes and susceptibility genes affecting transcription and chromatin-remodelling pathways have an important role behind the mechanism of the disease. But there are environmental factors also. Currently 40%-80% of autism cases are related to some risk genes, but epigenetic, particularly environmental modifiers, like advanced age of father, gestational complications and infections, prenatal exposure to anti-convulsants, or paucity of oestrogen in developmental brain are also playing fundamental roles in heterogeneity of manifestations. Till date, hundreds of genes have been recognized along with the environmental factors but how they interact to manifest the disease is still unknown due to complexities in interaction and overlap between different neuro-psychiatric disorders. Presence of second level modifiers has made the situation more multifaceted. However, advancements in sequencing technology, analyzing software, and expansion of databases have made the study of genetic modifiers possible. Going through the works by various scientists across the globe over the last 75 years, authors have identified a number of chromosomes, multitudes of gene loci, many genetic overlaps, and myriads of modifiers - endocrinal, environmental, and epigenetic. But, at the same time they have warned that though genes play a pivotal role, the other factors also need to be considered and studied in detail with proper attention and finally synthesis all the information reasonably to discover the root cause of autism.

Keywords: Autism; ASD; Neurodevelopmental Disorders; Neuro-psychiatric Disorders; Genetics; Epigenetics

References

1. Maenner MJ., et al. “Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2016”. (MMWR) Surveillance Summaries 69 (2020): 1-12.
2. Loomes R., et al. “What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis”. Journal of the American Academy of Child and Adolescent Psychiatry 56 (2017): 466-474.
3. Lai MC., et al. “Autism”. Lancet 383 (2014): 896-910.
4. Kanner L. “Autistic disturbances of affective contact”. Nervous Child 2 (1943): 217-250.
5. Chaste P and Leboyer M. “Autism risk factors: genes, environment, and gene-environment interactions”. Dialogues in Clinical Neuroscience 14 (2012): 281-292.
6. Constantino J N., et al. “Sibling recurrence and the genetic epidemiology of autism”. The American Journal of Psychiatry 167 (2010): 1349-1356.
7. Risch N., et al. “Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions”. The American Journal of Psychiatry 171 (2014): 1206-1213.
8. Sandin S., et al. “The familial risk of autism”. JAMA 311 (2014): 1770-1777.
9. “Full genome screen for autism with evidence for linkage to a region on chromosome 7q | human molecular genetics | oxford academic”. Human Molecular Genetics 7 (1998): 571-578.
10. International Molecular Genetic Study of Autism Consortium [IMGSAC]. “A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p”. American Journal of Human Genetics 69 (2001): 570-581.
11. Stern D., et al. “Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures”. Clinical Genetics 92 (2017): 221-223.
12. Woodbury-Smith M., et al. “Progress in the genetics of autism spectrum disorder”. Developmental Medicine and Child Neurology 60 (2018): 445-451.
13. Schmunk G and Gargus J J. “Channelopathy pathogenesis in autism spectrum disorders”. Frontiers in Genetics 4 (2013): 222.
14. Giovedí S., et al. “Involvement of synaptic genes in the pathogenesis of autism spectrum disorders: the case of synapsins”. Frontiers in Pediatrics 2 (2014): 94.
15. Stessman H A F., et al. “Targeted sequencing identifies 91 neurodevelopmental disorder risk genes with autism and developmental disability biases”. Nature Genetics 49 (2017): 515-526.
16. De Rubeis S., et al. “Synaptic, transcriptional and chromatin genes disrupted in autism”. Nature 515 (2014): 209-215.
17. Lim ET., et al. “Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder”. Nature Neuroscience 20 (2017): 1217-1224.
18. Ronemus M., et al. “The role of de novo mutations in the genetics of autism spectrum disorders”. Nature Reviews Genetics 15 (2014): 133-141.
19. Gilissen C., et al. “Genome sequencing identifies major causes of severe intellectual disability”. Nature 511 (2014): 344-347.
20. Pizzo L., et al. “Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants”. Genetic Medicine 21 (2016) 91:6-825.
21. The Autism Genome Project Consortium P., et al. “Mapping autism risk loci using genetic linkage and chromosomal rearrangements”. Nature Genetics 39 (2007): 319-328.
22. Duffney L J., et al. “Epigenetics and autism spectrum disorder: a report of an autism case with mutation in H1 linker histone HIST1H1E and literature review”. American Journal of Medical Genetics 177 (2018): 426-433.
23. Kubota T andMochizuki K. “Epigenetic effect of environmental factors on autism spectrum disorders”. International Journal of Environmental Research and Public Health 13 (2016): E504.
24. Cross-Disorder Group of the Psychiatric Genomics Consortium. “Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis”. Lancet 381 (2013): 1371-1379.
25. Cross-Disorder Group of the Psychiatric Genomics Consortium Lee SH., et al. “Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs”. Nature Genetics 45 (2013): 984-994.
26. Schork A J., et al. “A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment”. Nature Neuroscience 22 (2019): 353-361.
27. Khanzada N S., et al. “Gene Analytics pathway analysis and genetic overlap among autism spectrum disorder, bipolar disorder and schizophrenia”. International Journal of Molecular Sciences 18 (2017): E527.
28. Rapoport J., et al. “Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited”. Journal of the American Academy of Child and Adolescent Psychiatry 48 (2009): 10-18.
29. Sullivan P F., et al. “Family history of schizophrenia and bipolar disorder as risk factors for autism”. Archives of General Psychiatry 69 (2012): 1099-1103.
30. The Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium. “Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia”. Molecular Autism 8 (2017): 21.
31. Stergiakouli E., et al. “Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development”. Molecular Autism 8 (2017): 18.
32. Ohkawara T., et al. “Maternal viral infection during pregnancy impairs development of fetal serotonergic neurons”. Brain Development 37 (2015): 88-93.
33. Dufour-Rainfray D., et al. “Behavior and serotonergic disorders in rats exposed prenatally to valproate: a model for autism”. Neuroscience Letter 470 (2010): 55-59.
34. Nardone S and Elliott E. “The interaction between the immune system and epigenetics in the etiology of Autism Spectrum disorders”. Frontiers in Neuroscience 10 (2016): 329.
35. Rossignol DA and Frye RE. “A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures”. Molecular Psychiatry4 (2012): 389-401.
36. Siu MT and Weksberg R. “Epigenetics of Autism Spectrum Disorder”. Advances in Experimental Medicine and Biology 978 (2017): 63-90.
37. Dufour-Rainfray D., et al. “Fetal exposure to teratogens: evidence of genes involved in autism”. Neuroscience and Biobehavioral Reviews 5 (2011): 1254-1265.
38. Kim YS and Leventhal BL. “Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders”. Biological Psychiatry1 (2015): 66-74.
39. Lee KW., et al. “Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age”. Environmental Health Perspectives2 (2015): 193-199.
40. Roullet FI., et al. “In utero exposure to valproic acid and autism—a current review of clinical and animal studies”. Neurotoxicology and Teratology 36 (2013): 47-56.
41. Yaoi T., et al. “Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A”. Biochemical and Biophysical Research Communications 3 (2008): 563-567.
42. Gardener H., et al. “Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis”. Pediatrics 2 (2011): 344-355.
43. Grafodatskaya D., et al. “The health risks of ART”. EMBO Report2 (2013): 129-135.
44. DeBaun MR., et al. “Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19”. American Journal of Human Genetics1 (2003): 156-160.
45. Sutcliffe AG., et al. “Assisted reproductive therapies and imprinting disorders—a preliminary British survey”. Human Reproduction4 (2006): 1009-1011.
46. Froehlich-Santino W., et al. “Prenatal and perinatal risk factors in a twin study of autism spectrum disorders”. Journal of Psychiatric Research 54 (2014): 100-108.
47. Krakowiak P., et al. “Autism-specific maternal anti-fetal brain autoantibodies are associated with metabolic conditions”. Autism Research1 (2016): 89-98.
48. Li YM., et al. “Association between maternal obesity and autism spectrum disorder in offspring: a meta-analysis”. Journal of Autism and Developmental Disorders 1 (2016): 95-102.
49. Werling D M., et al. “Sex differences in autism spectrum disorders”. Current Opinion in Neurology 26 (2013): 146-153.
50. Desachy G., et al. “Increased female autosomal burden of rare copy number variants in human populations and in autism families”. Molecular Psychiatry 20 (2015): 170-175.
51. Ziats M N and Rennert O M. “Sex-biased gene expression in the developing brain: implications for autism spectrum disorders”. Molecular Autism 4 (2013): 10.
52. Baron-Cohen S., et al. “Sex differences in the brain: implications for explaining autism”. Science 310 (2005): 819-823.
53. Roved J., et al. “Sex differences in immune responses: hormonal effects, antagonistic selection, and evolutionary consequences”. Hormones and Behavior 88 (2017): 95-105.
54. Liu S., et al. “A rare variant identified within the GluN2B C-Terminus in a patient with autism affects NMDA receptor surface expression and spine density”. Journal of Neuroscience 37 (2017b): 4093-4102.
55. Liu X., et al. “Idiopathic autism: cellular and molecular phenotypes in pluripotent stem cell-derived neurons”. Molecular Neurobiology 54 (2017b): 4507-4523.
56. Rylaarsdam Lauren and Alicia Guemez-Gamboa. “Genetic Causes and Modifiers of Autism Spectrum Disorder”. Frontiers in Cellular Neuroscience 13 (2019): 385.

Citation

Citation: Sukanti Bhattacharyya., et al. “Is Genetics Implicated in the Causation of Autism?”.Acta Scientific Medical Sciences 6.3 (2022): 60-71.

Copyright

Copyright: © 2022 Sukanti Bhattacharyya., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.