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Uddin, M. Mutational Landscape of Autism Spectrum Disorder Brain Tissue. Encyclopedia. Available online: https://encyclopedia.pub/entry/19617 (accessed on 12 February 2026).
Uddin M. Mutational Landscape of Autism Spectrum Disorder Brain Tissue. Encyclopedia. Available at: https://encyclopedia.pub/entry/19617. Accessed February 12, 2026.
Uddin, Mohammed. "Mutational Landscape of Autism Spectrum Disorder Brain Tissue" Encyclopedia, https://encyclopedia.pub/entry/19617 (accessed February 12, 2026).
Uddin, M. (2022, February 18). Mutational Landscape of Autism Spectrum Disorder Brain Tissue. In Encyclopedia. https://encyclopedia.pub/entry/19617
Uddin, Mohammed. "Mutational Landscape of Autism Spectrum Disorder Brain Tissue." Encyclopedia. Web. 18 February, 2022.
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
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This entry is adapted from the peer-reviewed paper 10.3390/genes13020207

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of early childhood onset, characterized principally by socio-communicative impairments and certain restricted behavioural patterns, but also associated with other neuropsychiatric and medical conditions. Rare post-zygotic mutations in the brain are now known to contribute to several neurodevelopmental disorders, including autism spectrum disorder (ASD). However, due to the limited availability of brain tissue, most studies rely on estimates of mosaicism from peripheral samples.

exome sequencing post-zygotic somatic germline brain tissue autism spectrum disorder (ASD)

1. Introduction

The genetic underpinning of this disorder is rapidly evolving, and the exact genetic mechanisms are complex and not fully understood, despite many ASD-implicated genes having been identified [1][2][3][4]. In brief, rare, particularly de novo, single nucleotide variants (SNV) and copy number variants (CNV) of variable size are implicated. These variants, whether SNVs or CNVs, are often variable in their penetrance and consequently almost certainly act in concert with each other and with other epigenetic and non-genetic factors. Moreover, genetic variants that are more commonly observed in the population (‘common variants’, minor allele frequency [MAF] ~1% or more) also play a role, but their discovery for ASD has lagged behind other neurodevelopmental and neuropsychiatric disorders [5]. The relative contribution of these different genetic factors and other non-genetic factors in any one individual is unclear, although cases have been described of Mendelian, or otherwise highly penetrant, single-gene/locus mutations [6][7].
Many mutations occur in the germline, inherited or arising de novo in one parent’s germ cell. However, post-zygotic mutations (PZM) may also occur during foetal development or, indeed, at any stage among those cells that undergo division as part of their life-cycle. Consequently, these events give rise to distinct cell populations, identifiable in peripheral samples, such as blood by a variant allele fraction that deviates from the 0.5 that would be expected for a typical heterozygous mutation. Using this approach, study undertook ultra-deep sequencing of whole exomes from the Simons Simplex Collection and confirmed the contribution of genetic mosaicism to ASD [8]. Similarly, Lim and colleagues [9] investigated this using peripherally obtained DNA and determined that 7.5% of de novo mutations in ASD are post-zygotic, with particular genes enriched for these events.
For brain disorders, such mutations can also be directly identified in post-mortem brain tissue, a method that also allows a more detailed evaluation of their relationship to underlying histopathological abnormality and brain expression [10][11]. Such an approach has been able to identify PZMs in resected brain tissue from patients with ASD [11][12] and epilepsy [13]. Study using ultra-deep, whole-genome sequencing of 59 ASD donors, the enrichment of somatic SNVs was observed in neural enhancer sequences compared to 15 control donors [14]. This adds further weight to the evidence that post-zygotic mutations (PZMs) are important in ASD’s etiology and that they may shed light on specific pathophysiological mechanisms.
In order to further investigate the role of PZMs,the researchers used post-mortem brain samples from the Harvard Brain Tissue Resource Center (HBTRC), obtained through the Autism Tissue Program, to investigate the presence of post-zygotic mutations in ASD donors. Although there are potential challenges to extracting DNA from brain tissue,the researchers have previously demonstrated success [15], as well as shown how postmortem tissue can yield new, previously unidentified findings [16].

2. Mutational Landscape of Autism Spectrum Disorder Brain Tissue

Brain specimens are a rare resource in neurodevelopmental disorders but can uniquely provide insight into the genetic mechanisms of disease through the ability to directly study the very tissues that underlie the manifestations of these disorders [9][10][11][12][13][15]. This includes the ability to identify the tissue of specific post-zygotic mutations. Such mutations have for a long time been recognized as an important etiological factor in focal cortical dysplasias and epilepsy syndromes [13]. However, their role in other neurodevelopmental disorders, including ASD, has emerged [11][12][15]. Much of the evidence is based on the detection of alternate allele fraction (AAF) from the deep sequenced coverage of peripherally derived specimens. The researchers examined donated brain tissue from patients with ASD and identified PZMs in several genes that may be aetiologically implicated in their ASD diagnoses. Although none of the genes habouring predicted-damaging PZMs was previously implicated in ASD, intellectual disability (ID), or other neurodevelopmental disorders, two, TRAK1 and CLSTN3, are widely expressed in the brain.
TRAK1 is closely associated with DISC1, itself implicated in schizophrenia and neural development [17][18]. Mutations in DISC1 have been well documented in association with schizophrenia but not ASD. Additionally, one predicted pathogenic mutation in TRAK1 has also been described in the literature in a subject with schizophrenia [19]. The implications, therefore, for neurodevelopmental disorders such as ASD are unclear, although the genetic relationship between ASD and schizophrenia is now well-established [20]. Stronger evidence for a possible role in ASD phenotypes exists for CLSTN3, a calsyntenin, which as a group function as synaptogenic adhesion molecules [21][22]. Specifically, CLSTN3 is thought to be important for the normal development and function of the GABAergic and glutaminergic synapses, and although not specifically identified as an ASD-implicated gene, a de novo predicted damaging mutation in this gene has previously been described in an ASD proband [23]. Rodent models of CLSTN3 have identified the impact of deletion on impairing cognitive function [24], offering a possible pathophysiological mechanism.
In contrast tothe researchers search among the PZMs,the researchers did identify several germline mutations that are likely implicated in the ASD diagnoses of these subjects. For example, a mutation in PTEN was identified in one subject. PTEN is an overgrowth gene, with a variable phenotype that may include macrocephaly, tissue proliferation, including tumors, and neurodevelopmental disorders [25]. Indeed, research suggests that as many as 20% of individuals with autism who also are macrocephalic may have a PTEN mutation [26]. In another subject, a predicted damaging mutation in SCN1A was identified. SCN1A encodes the α-1 subunit of the NaV1.1 sodium channel and is strongly associated with epilepsy as one of the most important channelopathies [27][28]. Its most notable association is Dravet Syndrome, but other epilepsy and movement disorders have also been described, as has ASD, although the exact prevalence is unclear, and may be in the region of 24–40% [29].The researchers do not know if individual AN16115 had epilepsy during their lifetime.
The researchers also identified variants impacting CDH13 and CACNA1C. CDH13 is a Cadherin gene, a group of genes which encode a class of calcium-dependent transmembrane protein. Their embryonic expression earmarks the critical role they play in axonal growth and synapse development. Although there are many members of this protein superfamily, a small number have been described in association with neurodevelopmental phenotypes, including ASD and ADHD [30]. CACNA1C is another calcium channel protein, encoding the α-1c subunit of the L-type voltage-gated calcium channel. Common variants in this gene have been identified in association with several different neuropsychiatric phenotypes [31][32], including ASD [33]. Moreover, mouse models have suggested a role for this gene in potentially related cognitive endophenotypes that include fear conditioning [34]. It is quite possible, therefore, that these mutations also played an etiological role in the ASD diagnosis in these cases and further reinforce the importance of cadherins and a channelopathy-mediated pathogenesis in ASD.
Study was conducted to show the potential utility of studying patterns of mutation in brain tissue and specifically to identify post-zygotic mutations that may be of aetiological relevance. Althoughthe researchers failed to identify predicted damaging mutations in any known ASD or other neurodevelopmental genes,the researchers study has successfully identified post-zygotic mutations, including a small number in genes that warrant further investigation.The researchers results may alternatively suggest a less widespread role for PZMs than previously predicted. However, considering the emerging evidence from epilepsy and ASD discussed above, this seems unlikely. The small sample size of the study will have impacted on the power of this study to identify these variants. It is also possible that PZMs are of aetiological significance only for particular phenotypes, such as severe ASD, nonverbal ASD, or ASD with co-morbidities such as epilepsy. In the absence of phenotype information,the researchers are unable to further comment on this; however, moving forward, any brain tissue resource will need to also include detailed phenotype information to facilitate the unravelling of these brain-behaviour connections. Moreover,the researchers are not able to indicate whether undissected brain regions in these specimens are also negative for PZMs. As discussed in Wintle et al. [15]), the BA17 visual cortex was used for this study, in part due to its easy dissection and availability. Ideally, the search for PZMs will be predicated on the identification of histopathological abnormality, which will then motivate the decision on which regions of the brain to dissect.
The researchers hope thatthe researchers results will additionally provide a resource of genetic results on postmortem tissue in ASD patients. The nature of these mutations, including their mechanism, the genes impacted, and the potential effects on brain development will only be truly resolved with greater emphasis on studies such as this one that are also able to evaluate histology and cellular function in the tissues impacted. There are several ways in which studies such as this can make further progress. The establishment of tissue resources that are available to the scientific community are making samples available, allowing increased sample sizes, and these are often from patients who have detailed phenotype information. In considering sample size, there are a number of operational complexities in establishing a tissue resource. Samples may have to be collected from different geographic locations, and these may have been stored under different conditions. Detailed information will be needed on factors that may impact the results and their interpretation. Moreover, whereas on the one hand the tissue may comprise samples resected during surgery, for other families the tissue may have been donated after the death of a loved one. This requires a sensitive and ethical process to be in place. Consequently,the researchers anticipate that sample sizes will remain modest in comparison to other methodological approaches. This notwithstanding, the strength of this approach is the ability to directly identify PZMs in brain tissue as well as more closely study the impact of mutations in the tissue itself. In the future, it will be important to more carefully examine genetic architecture across different regions; this will be facilitated by using single cell genomic approaches. Additionally, it will be important to stratify samples by sex and developmental age, as well as to compare the genetic architecture between histologically normal and abnormal tissues.

References

  1. Woodbury-Smith, M.; Scherer, S.W. Progress in the genetics of autism spectrum disorder. Dev. Med. Child Neurol. 2018, 60, 445–451.
  2. Yuen, R.K.C.; Merico, D.; Bookman, M.; Howe, J.L.; Thiruvahindrapuram, B.; Patel, R.V.; Whitney, J.; Deflaux, N.; Bingham, J.; Wang, Z.; et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat. Neurosci. 2017, 20, 602–611.
  3. Zarrei, M.; Burton, C.L.; Engchuan, W.; Young, E.J.; Higginbotham, E.J.; MacDonald, J.R.; Trost, B.; Chan, A.J.S.; Walker, S.; Lamoureux, S.; et al. A large data resource of genomic copy number variation across neurodevelopmental disorders. NPJ Genom. Med. 2019, 4, 26.
  4. Trost, B.; Engchuan, W.; Nguyen, C.M.; Thiruvahindrapuram, B.; Dolzhenko, E.; Backstrom, I.; Mirceta, M.; Mojarad, B.A.; Yin, Y.; Dov, A.; et al. Genome-wide detection of tandem DNA repeats that are expanded in autism. Nature 2020, 586, 80–86.
  5. 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. Mol. Autism 2017, 8, 21.
  6. Saskin, A.; Fulginiti, V.; Birch, A.H.; Trakadis, Y. Prevalence of four Mendelian disorders associated with autism in 2392 affected families. J. Hum. Genet. 2017, 62, 657–659.
  7. Sanders, S.J.; He, X.; Willsey, A.J.; Ercan-Sencicek, A.G.; Samocha, K.E.; Cicek, A.E.; Murtha, M.T.; Bal, V.H.; Bishop, S.L.; Dong, S.; et al. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron 2015, 87, 1215–1233.
  8. Dou, Y.; Yang, X.; Li, Z.; Wang, S.; Zhang, Z.; Ye, A.Y.; Yan, L.; Yang, C.; Wu, Q.; Li, J.; et al. Postzygotic single-nucleotide mosaicisms contribute to the etiology of autism spectrum disorder and autistic traits and the origin of mutations. Hum. Mutat. 2017, 38, 1002–1013.
  9. Lim, E.T.; Uddin, M.; De Rubeis, S.; Chan, Y.; Kamumbu, A.S.; Zhang, X.; D’Gama, A.M.; Kim, S.N.; Hill, R.S.; Goldberg, A.P.; et al. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Nat. Neurosci. 2017, 20, 1217–1224.
  10. Keogh, M.J.; Wei, W.; Wilson, I.; Coxhead, J.; Ryan, S.; Rollinson, S.; Griffin, H.; Kurzawa-Akanbi, M.; Santibanez-Koref, M.; Talbot, K.; et al. Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource. Genome Res. 2017, 27, 165–173.
  11. D’Gama, A.M.; Pochareddy, S.; Li, M.; Jamuar, S.S.; Reiff, R.E.; Lam, A.N.; Sestan, N.; Walsh, C.A. Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. Neuron 2015, 88, 910–917.
  12. Alonso-Gonzalez, A.; Calaza, M.; Amigo, J.; Gonzalez-Penas, J.; Martinez-Regueiro, R.; Fernandez-Prieto, M.; Parellada, M.; Arango, C.; Rodriguez-Fontenla, C.; Carracedo, A.; et al. Exploring the biological role of postzygotic and germinal de novo mutations in ASD. Sci. Rep. 2021, 11, 319.
  13. Stosser, M.B.; Lindy, A.S.; Butler, E.; Retterer, K.; Piccirillo-Stosser, C.M.; Richard, G.; McKnight, D.A. High frequency of mosaic pathogenic variants in genes causing epilepsy-related neurodevelopmental disorders. Genet. Med. 2018, 20, 403–410.
  14. Rodin, R.E.; Dou, Y.; Kwon, M.; Sherman, M.A.; D’Gama, A.M.; Doan, R.N.; Rento, L.M.; Girskis, K.M.; Bohrson, C.L.; Kim, S.N.; et al. The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing. Nat. Neurosci. 2021, 24, 176–185.
  15. Wintle, R.F.; Lionel, A.C.; Hu, P.; Ginsberg, S.D.; Pinto, D.; Thiruvahindrapduram, B.; Wei, J.; Marshall, C.R.; Pickett, J.; Cook, E.H.; et al. A genotype resource for postmortem brain samples from the Autism Tissue Program. Autism Res. 2011, 4, 89–97.
  16. Uddin, M.; Woodbury-Smith, M.; Chan, A.; Brunga, L.; Lamoureux, S.; Pellecchia, G.; Yuen, R.K.C.; Faheem, M.; Stavropoulos, D.J.; Drake, J.; et al. Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes. Neurol. Genet. 2017, 3, e199.
  17. Ogawa, F.; Malavasi, E.L.; Crummie, D.K.; Eykelenboom, J.E.; Soares, D.C.; Mackie, S.; Porteous, D.J.; Millar, J.K. DISC1 complexes with TRAK1 and Miro1 to modulate anterograde axonal mitochondrial trafficking. Hum. Mol. Genet. 2014, 23, 906–919.
  18. Malavasi, E.L.V.; Economides, K.D.; Grunewald, E.; Makedonopoulou, P.; Gautier, P.; Mackie, S.; Murphy, L.C.; Murdoch, H.; Crummie, D.; Ogawa, F.; et al. DISC1 regulates N-methyl-D-aspartate receptor dynamics: Abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness. Transl. Psychiatry 2018, 8, 184.
  19. Xu, B.; Roos, J.L.; Dexheimer, P.; Boone, B.; Plummer, B.; Levy, S.; Gogos, J.A.; Karayiorgou, M. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat. Genet. 2011, 43, 864–868.
  20. Vissers, L.E.; Gilissen, C.; Veltman, J.A. Genetic studies in intellectual disability and related disorders. Nat. Rev. Genet. 2016, 17, 9–18.
  21. Um, J.W.; Pramanik, G.; Ko, J.S.; Song, M.Y.; Lee, D.; Kim, H.; Park, K.S.; Sudhof, T.C.; Tabuchi, K.; Ko, J. Calsyntenins function as synaptogenic adhesion molecules in concert with neurexins. Cell Rep. 2014, 6, 1096–1109.
  22. Pettem, K.L.; Yokomaku, D.; Luo, L.; Linhoff, M.W.; Prasad, T.; Connor, S.A.; Siddiqui, T.J.; Kawabe, H.; Chen, F.; Zhang, L.; et al. The specific α-neurexin interactor calsyntenin-3 promotes excitatory and inhibitory synapse development. Neuron 2013, 80, 113–128.
  23. Guo, H.; Duyzend, M.H.; Coe, B.P.; Baker, C.; Hoekzema, K.; Gerdts, J.; Turner, T.N.; Zody, M.C.; Beighley, J.S.; Murali, S.C.; et al. Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Genet. Med. 2019, 21, 1611–1620.
  24. Lipina, T.V.; Prasad, T.; Yokomaku, D.; Luo, L.; Connor, S.A.; Kawabe, H.; Wang, Y.T.; Brose, N.; Roder, J.C.; Craig, A.M. Cognitive Deficits in Calsyntenin-2-deficient Mice Associated with Reduced GABAergic Transmission. Neuropsychopharmacology 2016, 41, 802–810.
  25. Busch, R.M.; Srivastava, S.; Hogue, O.; Frazier, T.W.; Klaas, P.; Hardan, A.; Martinez-Agosto, J.A.; Sahin, M.; Eng, C.; Developmental Synaptopathies Consortium. Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN. Transl. Psychiatry 2019, 9, 253.
  26. Tan, M.H.; Mester, J.; Peterson, C.; Yang, Y.; Chen, J.L.; Rybicki, L.A.; Milas, K.; Pederson, H.; Remzi, B.; Orloff, M.S.; et al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am. J. Hum. Genet. 2011, 88, 42–56.
  27. Harkin, L.A.; McMahon, J.M.; Iona, X.; Dibbens, L.; Pelekanos, J.T.; Zuberi, S.M.; Sadleir, L.G.; Andermann, E.; Gill, D.; Farrell, K.; et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 2007, 130, 843–852.
  28. Scheffer, I.E.; Nabbout, R. SCN1A-related phenotypes: Epilepsy and beyond. Epilepsia 2019, 60 (Suppl. S3), S17–S24.
  29. Ouss, L.; Leunen, D.; Laschet, J.; Chemaly, N.; Barcia, G.; Losito, E.M.; Aouidad, A.; Barrault, Z.; Desguerre, I.; Breuillard, D.; et al. Autism spectrum disorder and cognitive profile in children with Dravet syndrome: Delineation of a specific phenotype. Epilepsia Open 2019, 4, 40–53.
  30. Hawi, Z.; Tong, J.; Dark, C.; Yates, H.; Johnson, B.; Bellgrove, M.A. The role of cadherin genes in five major psychiatric disorders: A literature update. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2018, 177, 168–180.
  31. Moon, A.L.; Haan, N.; Wilkinson, L.S.; Thomas, K.L.; Hall, J. CACNA1C: Association with Psychiatric Disorders, Behavior, and Neurogenesis. Schizophr. Bull. 2018, 44, 958–965.
  32. Sykes, L.; Haddon, J.; Lancaster, T.M.; Sykes, A.; Azzouni, K.; Ihssen, N.; Moon, A.L.; Lin, T.E.; Linden, D.E.; Owen, M.J.; et al. Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species. Schizophr. Bull. 2019, 45, 1024–1032.
  33. Li, J.; Zhao, L.; You, Y.; Lu, T.; Jia, M.; Yu, H.; Ruan, Y.; Yue, W.; Liu, J.; Lu, L.; et al. Schizophrenia Related Variants in CACNA1C also Confer Risk of Autism. PLoS ONE 2015, 10, e0133247.
  34. Shinnick-Gallagher, P.; McKernan, M.G.; Xie, J.; Zinebi, F. L-type voltage-gated calcium channels are involved in the in vivo and in vitro expression of fear conditioning. Ann. N. Y. Acad. Sci. 2003, 985, 135–149.
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