Epigenetics of autism

One of the leading theories of a potential pathogenic process in autism is cortical hyperexcitability. Maintaining proper levels of cortical excitability is essential for many important cognitive functions, such as processing sensory information,{{Cite journal |last=Fries |first=Pascal |date=2005 |title=A mechanism for cognitive dynamics: neuronal communication through neuronal coherence |url=https://pubmed.ncbi.nlm.nih.gov/16150631/ |journal=Trends in Cognitive Sciences |volume=9 |issue=10 |pages=474–480 |doi=10.1016/j.tics.2005.08.011 |issn=1364-6613 |pmid=16150631|s2cid=6275292 }} communication between different regions of the brain, and neural plasticity.{{Cite journal |last1=Takarae |first1=Yukari |last2=Sweeney |first2=John |date=2017-10-13 |title=Neural Hyperexcitability in Autism Spectrum Disorders |journal=Brain Sciences |volume=7 |issue=10 |pages=129 |doi=10.3390/brainsci7100129 |issn=2076-3425 |pmc=5664056 |pmid=29027913|doi-access=free }} Hyperexcitability can disrupt these functions and thereby alter cognitive dynamism in important ways. For example, cortical hyperexcitability can affect how the duration of sensory stimuli are perceived. A common trait of autism is reduced somatosensory functioning, which has been linked to alterations in cortical hyperexcitability in autistic individuals.{{Cite journal |last1=Puts |first1=Nicolaas A. J. |last2=Wodka |first2=Ericka L. |last3=Harris |first3=Ashley D. |last4=Crocetti |first4=Deana |last5=Tommerdahl |first5=Mark |last6=Mostofsky |first6=Stewart H. |last7=Edden |first7=Richard A. E. |date=2017 |title=Reduced GABA and altered somatosensory function in children with autism spectrum disorder |journal=Autism Research|volume=10 |issue=4 |pages=608–619 |doi=10.1002/aur.1691 |issn=1939-3806 |pmc=5344784 |pmid=27611990}} Cortical hyperexcitability can also alter how "old" and "new" stimuli are perceived by changing habituation and adaptation processes in the brain. Altered habituation processes have been linked to characteristic traits of autism, such as under-responsiveness to some stimuli and over-responsiveness to others.{{Cite journal |last1=Guiraud |first1=Jeanne A. |last2=Kushnerenko |first2=Elena |last3=Tomalski |first3=Przemyslaw |last4=Davies |first4=Kim |last5=Ribeiro |first5=Helena |last6=Johnson |first6=Mark H. |last7=BASIS Team |date=2011-11-16 |title=Differential habituation to repeated sounds in infants at high risk for autism |url=https://pubmed.ncbi.nlm.nih.gov/21934535/ |journal=NeuroReport |volume=22 |issue=16 |pages=845–849 |doi=10.1097/WNR.0b013e32834c0bec |issn=1473-558X |pmid=21934535|s2cid=12868661 }}

There are many genetic and epigenetic factors that can contribute to increased excitability, but one of the mechanisms implicated in autism is alterations in GABAergic systems in the cortex. GABA is the main neurotransmitter implicated in inhibition in the cortex of mammalian brains;{{Cite journal |last=Petroff |first=Ognen A. C. |date=2002 |title=GABA and glutamate in the human brain |url=https://pubmed.ncbi.nlm.nih.gov/12467378/ |journal=The Neuroscientist |volume=8 |issue=6 |pages=562–573 |doi=10.1177/1073858402238515 |issn=1073-8584 |pmid=12467378|s2cid=84891972 }} changes to this cortical inhibitory system can result in increased excitability. Alterations in this system have been associated not only with autism but also with several other psychiatric conditions, such as major depressive disorder (MDD) and schizophrenia.{{Cite journal |last1=Schür |first1=Remmelt R. |last2=Draisma |first2=Luc W. R. |last3=Wijnen |first3=Jannie P. |last4=Boks |first4=Marco P. |last5=Koevoets |first5=Martijn G. J. C. |last6=Joëls |first6=Marian |last7=Klomp |first7=Dennis W. |last8=Kahn |first8=René S. |last9=Vinkers |first9=Christiaan H. |date=2016 |title=Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies |journal=Human Brain Mapping |volume=37 |issue=9 |pages=3337–3352 |doi=10.1002/hbm.23244 |issn=1097-0193 |pmc=6867515 |pmid=27145016}}

Alterations in the GABAergic system can occur through several epigenetic mechanisms, including modification of chromosome 15q11 to q13 regions which cause reduced levels of GABA signaling.{{Cite journal |last1=Grafodatskaya |first1=Daria |last2=Chung |first2=Brian |last3=Szatmari |first3=Peter |last4=Weksberg |first4=Rosanna |date=2010 |title=Autism spectrum disorders and epigenetics |url=https://pubmed.ncbi.nlm.nih.gov/20643313/ |journal=Journal of the American Academy of Child and Adolescent Psychiatry |volume=49 |issue=8 |pages=794–809 |doi=10.1016/j.jaac.2010.05.005 |issn=1527-5418 |pmid=20643313}} Cortical excitability can also be increased by modifications in the glutamatergic system.

Chromosome 15q11-13 contain genes encoding subunits of GABA receptors, and both deletion and duplication of this region can lead to cortical hyperexcitability. Duplications of 15q11-13 are associated with about 5% of autistic people{{cite journal |author=Schanen N. C. |date=2006 |title=Epigenetics of autism spectrum disorders |journal=Human Molecular Genetics |volume=15 |pages=R138–R150 |doi=10.1093/hmg/ddl213 |pmid=16987877 |doi-access=}} and about 1% of people diagnosed with classical autism.{{cite journal |author=Samaco, R. C. |author2=Hogart, A. |author3=LaSalle, J. M. |name-list-style=amp |date=2005 |title=Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3 |journal=Human Molecular Genetics |volume=14 |issue=4 |pages=483–492 |doi=10.1093/hmg/ddi045 |pmc=1224722 |pmid=15615769}} 15q11-13 in humans contains a cluster of genetically imprinted genes related to neurodevelopment. Like other genetically imprinted genes, the parent of origin determines the phenotypes associated with 15q11-13 duplications.{{cite journal |author=Cook, E.H. Jr. |author2=Lindgren, V. |author3=Leventhal, B.L. |author4=Courchesne, R. |author5=Lincoln, A. |author6=Shulman, C. |author7=Lord, C. |author8=Courchesne, E. |name-list-style=amp |date=1997 |title=Autism or atypical autism in maternally but not paternally derived proximal 15q duplication |journal=American Journal of Human Genetics |volume=60 |issue=4 |pages=928–934 |pmc=1712464 |pmid=9106540}} "Parent of origin effects" cause gene expression to occur only from one of the two copies of alleles that individuals receive from their parents. (For example, MKRN3 shows a parent of origin effect and is paternally imprinted. This means that only the MKRN3 allele received from the paternal side will be expressed.) Duplications in the maternal copy lead to a distinct condition that often includes autism.

Genes that are deficient in paternal or maternal 15q11-13 alleles result in Prader-Willi or Angelman syndromes, respectively, both of which are linked to high incidence of autism. Overexpression of maternally imprinted genes is predicted to cause autism, which focuses attention to the maternally expressed genes on 15q11-13, although it is still possible that alterations in the expression of both imprinted and bilallelically expressed genes contribute to these conditions.{{cite journal |author=Hogart, A. |date=2009 |title=Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alteration in gene expression not predicted from copy number |journal=Journal of Medical Genetics |volume=46 |issue=2 |pages=86–93 |doi=10.1136/jmg.2008.061580 |pmc=2634820 |pmid=18835857}} The commonly duplicated region of chromosome 15 also includes paternally imprinted genes that can be considered candidates for autism.

Members of the GABA receptor family, especially GABRB3, are attractive candidate genes for Autism because of their function in the nervous system. GABRB3 null mice exhibit behaviors consistent with autism{{cite journal |author=Klose, R.J. |author2=Bird, A.P. |name-list-style=amp |date=2006 |title=Genomic DNA methylation: the mark and its mediators |journal=Trends in Biochemical Sciences |volume=31 |issue=2 |pages=89–97 |doi=10.1016/j.tibs.2005.12.008 |pmid=16403636}} and multiple genetic studies have found significant evidence for association.{{cite journal |author=Kriaucionis, S. |author2=Bird, A. |name-list-style=amp |date=2003 |title=DNA methylation and Rett syndrome |journal=Human Molecular Genetics |volume=12 |issue=2 |pages=R221–R227 |doi=10.1093/hmg/ddg286 |pmid=12928486|doi-access=free }} Furthermore, a significant decrease in abundance of GABRB3 has been reported in the brains of autistic people and people with Rett syndrome.{{cite journal |author=Pickles, A. |author2=Bolton, P. |author3=Macdonald, H. |author4=Bailey, A. |author5=Le Couteur, A. |author6=Sim, C.H. |author7=Rutter, M. |name-list-style=amp |date=1995 |title=Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism |journal=American Journal of Human Genetics |volume=57 |issue=3 |pages=717–726 |pmc=1801262 |pmid=7668301}} Other GABA receptors residing on different chromosomes have also been associated with autism (e.g. GABRA4 and GABRB1 on chromosome 4p).{{cite journal |author=Ma, D.Q. |author2=Whitehead, P.L. |author3=Menold, M.M. |author4=Martin, E.R. |author5=Ashley-Koch, A.E. |author6=Mei, H. |author7=Ritchie, M.D. |author8=Delong, G.R. |author9=Abramson, R.K. |author10=Wright, H.H. |display-authors=etal |date=2005 |title=Identification of significant association and gene – gene interaction of GABA receptor subunit genes in autism |journal=American Journal of Human Genetics |volume=77 |issue=3 |pages=377–388 |doi=10.1086/433195 |pmc=1226204 |pmid=16080114}}

Regulation of gene expression in the 15q11-13 is rather complex and involves a variety of mechanisms such as DNA methylation, non-coding and anti-sense RNA.{{cite journal |author=Nicholls, R.D. |author2=Knepper, J.L. |name-list-style=amp |date=2001 |title=Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes |journal=Annu. Rev. Genom. Hum. Genet. |volume=2 |pages=153–175 |doi=10.1146/annurev.genom.2.1.153 |pmid=11701647}}

The imprinted genes of 15q11-13 are under the control of a common regulatory sequence, the imprinting control region (ICR). The ICR is a differentially methylated CpG island at the 5' end of SNRPN. It is heavily methylated on the silent maternal allele and unmethylated on the active paternal allele.{{cite journal |author=Hogart, A. |display-authors=etal |date=Feb 2009 |title=Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number |journal=Journal of Medical Genetics |volume=46 |issue=2 |pages=86–93 |doi=10.1136/jmg.2008.061580 |pmc=2634820 |pmid=18835857}}

MeCP2, which is a candidate gene for Rett syndrome, has been shown to affect regulation of expression in 15q11-13. Altered (decreased) expression of UBE3A and GABRB3 is observed in MeCP2 deficient mice and autistic people. This effect seems to happen without MeCP2 directly binding to the promoters of UBE3A and GABRB3. (Mechanism unknown) However, chromatin immunoprecipitation and bisulfite sequencing have demonstrated that MeCP2 binds to methylated CpG sites within GABRB3 and the promoter of SNRPN/SNURF.

Furthermore, homologous 15q11-13 pairing in neurons that is disrupted in RTT and autistic people, has been shown to depend on MeCP2.{{cite journal |author=Hogart, A. |display-authors=etal |date=2007 |title=15q11-13 gabaa receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism spectrum disorders |journal=Human Molecular Genetics |volume=16 |issue=6 |pages=691–703 |doi=10.1093/hmg/ddm014 |pmc=1934608 |pmid=17339270}} Combined, these data suggest a role for MeCP2 in the regulation of imprinted and biallelic genes in 15q11-13. However, evidently, it does not play a role in the maintenance of imprinting.

One current theory of the pathophysiology of autism is that it arises from a deficit in the folate-methionine pathway.{{Cite journal |last=Rai |first=Vandana |date=2016-03-08 |title=Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility |url=http://dx.doi.org/10.1007/s11011-016-9815-0 |journal=Metabolic Brain Disease |volume=31 |issue=4 |pages=727–735 |doi=10.1007/s11011-016-9815-0 |pmid=26956130 |s2cid=2740172 |issn=0885-7490|url-access=subscription }} Folate donates methyl groups to convert homocysteine into methionine, which is the precursor of S-adenosylmethionine. S-adenosylmethionine is the methyl group donor responsible for DNA and histone methylation.{{Cite journal |last=Lintas |first=C. |date=February 2019 |title=Linking genetics to epigenetics: The role of folate and folate-related pathways in neurodevelopmental disorders |url=https://pubmed.ncbi.nlm.nih.gov/30047142/ |journal=Clinical Genetics |volume=95 |issue=2 |pages=241–252 |doi=10.1111/cge.13421 |issn=1399-0004 |pmid=30047142|s2cid=51719484 }} Epigenetic changes can result in changed gene expression of pathway enzymes resulting in a change in folate levels which can contribute to autism. These changes to the epigenetic regulation interact with the pregnant woman's immune system activation and can result in an autism phenotype in the fetus' brain.{{Cite journal |last1=Nardone |first1=Stefano |last2=Elliott |first2=Evan |date=2016-07-12 |title=The Interaction between the Immune System and Epigenetics in the Etiology of Autism Spectrum Disorders |journal=Frontiers in Neuroscience |volume=10 |page=329 |doi=10.3389/fnins.2016.00329 |pmid=27462204 |pmc=4940387 |issn=1662-453X|doi-access=free }} To add, low levels of folate in the pregnant woman are correlated with DNA hypomethylation in the fetus.

The gene MTHFR codes for the enzyme methylenetetrahydrofolate reductase which is necessary for the synthesis of 5-methyl-tetrahydrofolate, a biologically active form of folate One important factor that has been identified for autism is polymorphism in MTHFR. A meta-analysis demonstrated that polymorphism of the MTHFR C677T genotype is correlated with an autism diagnosis in children from countries lacking food fortification.{{Cite journal |last1=Pu |first1=Danhua |last2=Shen |first2=Yiping |last3=Wu |first3=Jie |date=2013-05-07 |title=Association between MTHFR Gene Polymorphisms and the Risk of Autism Spectrum Disorders: A Meta-Analysis |url=http://dx.doi.org/10.1002/aur.1300 |journal=Autism Research |volume=6 |issue=5 |pages=384–392 |doi=10.1002/aur.1300 |pmid=23653228 |s2cid=41587673 |issn=1939-3792|url-access=subscription }}

While MTHFR is a proposed genetic factor for autism, there is limited clinical evidence from testing for MTHFR gene polymorphisms in the diagnostic setting.{{Cite journal |last1=Long |first1=Sarah |last2=Goldblatt |first2=Jack |date=2016 |title=MTHFR genetic testing: Controversy and clinical implications |url=https://pubmed.ncbi.nlm.nih.gov/27052143 |journal=Australian Family Physician |volume=45 |issue=4 |pages=237–240 |issn=0300-8495 |pmid=27052143}} The reason for these complications may be due to other modifiers of the folate metabolism pathway or other genes included in the pathway. Additionally, the levels of homocysteine (HCy) seem to result in an increased utility of the folate metabolism pathway as a predictor for autism diagnosis.{{Cite journal |last1=Shaik Mohammad |first1=Naushad |last2=Sai Shruti |first2=P. |last3=Bharathi |first3=Venkat |last4=Krishna Prasad |first4=Chintakindi |last5=Hussain |first5=Tajamul |last6=Alrokayan |first6=Salman A. |last7=Naik |first7=Usha |last8=Radha Rama Devi |first8=Akella |date=2016 |title=Clinical utility of folate pathway genetic polymorphisms in the diagnosis of autism spectrum disorders |url=http://dx.doi.org/10.1097/ypg.0000000000000152 |journal=Psychiatric Genetics |volume=26 |issue=6 |pages=281–286 |doi=10.1097/ypg.0000000000000152 |pmid=27755291 |s2cid=24163298 |issn=0955-8829|url-access=subscription }}

If the fetus is exposed to the mood stabilizer drug valproate (VPA), the likelihood of autism as well as other developmental anomalies (decreased intrauterine growth, spina bifida, limb defects, craniofacial defects, etc.) is increased.{{Cite journal |last=Ornoy |first=Asher |date=2009 |title=Valproic acid in pregnancy: How much are we endangering the embryo and fetus? |url=http://dx.doi.org/10.1016/j.reprotox.2009.02.014 |journal=Reproductive Toxicology |volume=28 |issue=1 |pages=1–10 |doi=10.1016/j.reprotox.2009.02.014 |pmid=19490988 |bibcode=2009RepTx..28....1O |issn=0890-6238|url-access=subscription }} VPA is an anticonvulsant drug commonly administered for generalized and partial seizures, but also for the treatment of migraines and bipolar mood disorder. Its mechanisms of action are varied, including enhanced GABA neurotransmission, modified inositol metabolism, and interaction with the ERK and Wnt/B-catenin signaling systems.{{Cite journal |last=Rosenberg |first=G. |date=2007-05-18 |title=The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? |url=http://dx.doi.org/10.1007/s00018-007-7079-x |journal=Cellular and Molecular Life Sciences |volume=64 |issue=16 |pages=2090–2103 |doi=10.1007/s00018-007-7079-x |pmid=17514356 |s2cid=91568 |issn=1420-682X|pmc=11149473 }} If taken while pregnant, the likelihood of autism is 8.9% to 10.8%. When VPA and another antiepileptic drug are taken, the likelihood increases to 11.7%.{{Cite journal |last=Moore |first=S J |date=2000-07-01 |title=A clinical study of 57 children with fetal anticonvulsant syndromes |url=http://dx.doi.org/10.1136/jmg.37.7.489 |journal=Journal of Medical Genetics |volume=37 |issue=7 |pages=489–497 |doi=10.1136/jmg.37.7.489 |pmid=10882750 |pmc=1734633 |issn=1468-6244}}{{Cite journal |last1=Rasalam |first1=AD |last2=Hailey |first2=H |last3=Williams |first3=JHG |last4=Moore |first4=SJ |last5=Turnpenny |first5=PD |last6=Lloyd |first6=DJ |last7=Dean |first7=JCS |date=2005-07-14 |title=Characteristics of fetal anticonvulsant syndrome associated autistic disorder |url=http://dx.doi.org/10.1017/s0012162205001076 |journal=Developmental Medicine & Child Neurology |volume=47 |issue=8 |pages=551–555 |doi=10.1017/s0012162205001076 |pmid=16108456 |issn=0012-1622|url-access=subscription }} Compared to the general population, this likelihood of autism is 16 times higher.{{Citation |last1=Fombonne |first1=Eric |title=Epidemiology of Pervasive Developmental Disorders |date=2011 |url=http://dx.doi.org/10.1093/med/9780195371826.003.0007 |work=Autism Spectrum Disorders |pages=90–111 |publisher=Oxford University Press |access-date=2022-04-11 |last2=Quirke |first2=Sara |last3=Hagen |first3=Arlene|doi=10.1093/med/9780195371826.003.0007 |isbn=978-0-19-537182-6 |url-access=subscription }}

Currently, there are two proposed epigenetic mechanisms for VPA increasing the likelihood in autism: alteration in folate metabolism and HDAC inhibition. VPA is a weak HDAC inhibitor. The VPA model discerns the potential pathogenesis and mechanisms of action of autism in animal models. HDAC inhibition is the most understood. In animal models, mice prenatally exposed to VPA had transient hyperacetylation of histones H3 and H4, decreased HDACs, and developed autism-like characteristics.{{Cite journal |last1=Tseng |first1=Chieh-En Jane |last2=McDougle |first2=Christopher J. |last3=Hooker |first3=Jacob M. |last4=Zürcher |first4=Nicole R. |date=2021 |title=Epigenetics of Autism Spectrum Disorder: Histone Deacetylases |url=https://linkinghub.elsevier.com/retrieve/pii/S0006322321018321 |journal=Biological Psychiatry |volume=91 |issue=11 |language=en |pages=922–933 |doi=10.1016/j.biopsych.2021.11.021|pmid=35120709 |s2cid=245010600 |url-access=subscription }} However, mice prenatally exposed to valpromide, analogous to VPA but not an HDAC inhibitor, did not experience transient hyperacetylation of histones H3 and H4 and did not develop autism-like characteristics.{{Cite journal |last1=Nicolini |first1=Chiara |last2=Fahnestock |first2=Margaret |date=2018 |title=The valproic acid-induced rodent model of autism |url=https://linkinghub.elsevier.com/retrieve/pii/S0014488617301103 |journal=Experimental Neurology |language=en |volume=299 |issue=Pt A |pages=217–227 |doi=10.1016/j.expneurol.2017.04.017|pmid=28472621 |s2cid=4914709 |url-access=subscription }} An important thing to note is the time of VPA. In the animal models, the significant effects of VPA in causing autism-like characteristics was demonstrated mainly in rats exposed to VPA on gestation day 12.5, not in other gestation days like day 9, 14.5, etc. The autism-like characteristics of mice included decreased distressed pup calls, decreased social exploration, decreased social behaviors, increased stereotypic locomotion, decreased acoustic prepulse inhibition, and increased sensitivity to non-painful stimuli.

This same association was replicated in the longitudinal studies. Children prenatally exposed to VPA or with fetal valproate syndrome (FVS) have a higher prevalence of autism. FVS is a rare condition in children that happens due to VPA exposure during the first trimester of pregnancy.

Romidepsin and MS-275, both HDAC inhibitors, improve social preference, which is the preference of social stimuli over non social stimuli, and interaction times of SHANK 3 deficient mice. Trichostatin A (TSA) is another example of an HDAC inhibitor. It results in increased histone acetylation at the oxytocin and vasopressin receptors of the nucleus accumbens (NA) in female voles, increasing pair bonding. In a small clinical trial, beta hydroxybutyrate, a product of the ketogenic diet and inhibitor of class 1 HDACs, has shown promise in improving the social behavior and skills in autistic children.'The inhibition of HDAC is correlated with overexpression of other genes.{{Cite journal |last1=Phiel |first1=Christopher J. |last2=Zhang |first2=Fang |last3=Huang |first3=Eric Y. |last4=Guenther |first4=Matthew G. |last5=Lazar |first5=Mitchell A. |last6=Klein |first6=Peter S. |date=2001 |title=Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen |journal=Journal of Biological Chemistry |volume=276 |issue=39 |pages=36734–36741 |doi=10.1074/jbc.m101287200 |pmid=11473107 |issn=0021-9258|doi-access=free }} Treatment of mice with valproate also increases hippocampal histone H3 acetylation.{{Cite journal |last1=Yildirim |first1=Emre |last2=Zhang |first2=Zhijing |last3=Uz |first3=Tolga |last4=Chen |first4=Chang-qing |last5=Manev |first5=Radmila |last6=Manev |first6=Hari |date=2003 |title=Valproate administration to mice increases histone acetylation and 5-lipoxygenase content in the hippocampus |url=http://dx.doi.org/10.1016/s0304-3940(03)00490-7 |journal=Neuroscience Letters |volume=345 |issue=2 |pages=141–143 |doi=10.1016/s0304-3940(03)00490-7 |pmid=12821190 |s2cid=22901763 |issn=0304-3940|url-access=subscription }}

Current candidate genes relating to autism in mice exposed to valproate in utero are NRXN1, NRXN2, NRXN3, NLGN1, NLGN2, and NLGN3. In the somatosensory cortex, CA1, dentate gyrus, and hippocampus, NLGN3 is significantly downregulated in mice treated with valproate.{{Cite journal |last=Brose |first=Nils |date=2009-08-28 |title=Faculty Opinions recommendation of Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. |doi=10.3410/f.1163641.625408 |doi-access=free}} While this evidence of NLGN3 downregulation due to valproate suggests a potential relevant mechanism for autism, further research is needed.

SHANK proteins are scaffolding proteins at glutamatergic synapses crucial for synaptic development. The disruption of SHANK genes is associated with neurocognitive impairments and conditions. The disruptions, either from mutations or deletions, are associated with conditions such as Phelan-McDermid syndrome (PMS), schizophrenia, and autism. SHANK 3 is the most studied gene from the SHANK gene family. Several studies have found that disruptions to SHANK 3 cause more severe cognitive impairments than disruptions to SHANK 1 or 2. These findings suggest that the SHANK gene that is disrupted may determine the severity of the cognitive impairments.{{Cite journal |last1=Monteiro |first1=Patricia |last2=Feng |first2=Guoping |date=2017 |title=SHANK proteins: roles at the synapse and in autism spectrum disorder |url=https://www.nature.com/articles/nrn.2016.183 |journal=Nature Reviews Neuroscience |language=en |volume=18 |issue=3 |pages=147–157 |doi=10.1038/nrn.2016.183 |pmid=28179641 |hdl=1822/50698 |s2cid=30562157 |issn=1471-0048|hdl-access=free }}

A study on two mutant mice lines, one line with an autism-linked SHANK 3 mutation on exon 21 and the other with a schizophrenia-linked SHANK 3 mutation on exon 21, found differences in the synaptic and behavioral impairments caused by disruptions to SHANK 3. The autism-linked mutation results in a complete loss of SHANK 3 (like a deletion) and impaired striatal synaptic transmission. The schizophrenia-linked mutation results in a truncated SHANK 3 protein and severe synaptic impairments in the prefrontal cortex.

Other studies suggest that SHANK3 knockout mice display behavioral phenotypes of autism. These mice display self-injurious grooming, anxiety, and social difficulties. Restoration of SHANK 3 in adult mice improved social difficulties and self-grooming behaviors. These findings indicate the potential therapeutic effect of restoring SHANK 3. SHANK 3 restoration may alleviate some characteristics of autism. In addition, modulators and proteins associated with SHANK 3 are potential therapeutic targets for autism. However, the effects of targeting modulators differ depending on the specific SHANK 3 disruption. For instance, studies have shown that increasing mGluR5 activity improved self grooming and behavioral differences. Yet, other studies have shown the opposite effect. This demonstrates that the therapeutic effects are dependent on specific SHANK 3 mutation.

There is a definite gender bias in the distribution of autism. There are about four times as many affected males across the autistic population. Even when people with mutations in X-linked genes (MECP2 and FMR1) are excluded, the gender bias remains. However, when only looking at people with the most severe cognitive impairment, the gender bias is not as extreme. While the most obvious conclusion is that an X-linked gene of major effect is involved in contributing to autism, the mechanism appears to be much more complex and perhaps epigenetic in origin.

Based on the results of a study on females with Turner syndrome, a hypothesis involving epigenetic mechanisms was proposed to help describe the gender bias of autism. People with Turner syndrome have only one X chromosome which can be either maternal or paternal in origin. When 80 females with monosomy X were tested for measures of social cognition, the people with a paternally derived X chromosome performed better than those with a maternally derived X chromosome. Males have only one X chromosome, derived from their mother. If a gene on the paternal X chromosome confers improved social skills, males are deficient in the gene. This could explain why males are more likely to be diagnosed with autism.{{cite journal |author=Skuse, D.H. |author2=James, R.S. |author3=Bishop, D.V. |author4=Coppin, B. |author5=Dalton, P. |author6=Aamodt-Leeper, G. |author7=Bacarese-Hamilton, M. |author8=Creswell, C. |author9=McGurk, R. |author10=Jacobs, P.A. |name-list-style=amp |date=1997 |title=Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function |url=https://ora.ox.ac.uk/objects/uuid:b45819a1-50b2-41aa-957c-e1f54736b335 |journal=Nature |volume=387 |issue=6634 |pages=705–708 |bibcode=1997Natur.387..705S |doi=10.1038/42706 |pmid=9192895 |doi-access=free |s2cid=4279874}}

In the proposed model, the candidate gene is silenced on the maternal copy of the X chromosome. Thus, males do not express this gene and are more susceptible to subsequent difficulties in social and communication skills. Females, on the other hand, are more resistant to autism.{{cite journal |author=Skuse, D. H. |date=2000 |title=Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism |journal=Pediatric Research |volume=47 |issue=1 |pages=9–16 |doi=10.1203/00006450-200001000-00006 |pmid=10625077 |doi-access=free}}{{cite journal |author=El Abd, S. |author2=Patton, M.A. |author3=Turk, J. |author4=Hoey, H. |author5=Howlin, P. |name-list-style=amp |date=1999 |title=Social, communicational, and behavioral deficits associated with ring X turner syndrome |journal=American Journal of Medical Genetics |volume=88 |issue=5 |pages=510–516 |doi=10.1002/(SICI)1096-8628(19991015)88:5<510::AID-AJMG14>3.0.CO;2-Z |pmid=10490708}}{{cite journal |author=Telvi, L. |author2=Lebbar, A. |author3=Del Pino, O. |author4=Barbet, J.P. |author5=Chaussain, J.L. |name-list-style=amp |date=1999 |title=45,X/46,XY mosaicism: report of 27 cases |journal=Pediatrics |volume=104 |issue=2 Pt 1 |pages=304–308 |doi=10.1542/peds.104.2.304 |pmid=10429013 |s2cid=24428373}}{{cite journal |author=Donnelly, S.L. |author2=Wolpert, C.M. |author3=Menold, M.M. |author4=Bass, M.P. |author5=Gilbert, J.R. |author6=Cuccaro, M.L. |author7=Delong, G.R. |author8=Pericak-Vance, M.A. |name-list-style=amp |date=2000 |title=Female with autistic disorder and monosomy X (Turner syndrome): parent-of-origin effect of the X chromosome |journal=American Journal of Medical Genetics |volume=96 |issue=3 |pages=312–316 |doi=10.1002/1096-8628(20000612)96:3<312::AID-AJMG16>3.0.CO;2-8 |pmid=10898907}} Recently a cluster of imprinted genes on the mouse X chromosome was discovered; the paternal allele was expressed while the female copy was imprinted and silenced.{{cite journal |author=William Davies |author2=Anthony Isles |author3=Rachel Smith |author4=Delicia Karunadasa |author5=Doreen Burrmann |author6=Trevor Humby |author7=Obah Ojarikre |author8=Carol Biggin |author9=David Skuse |author10=Paul Burgoyne |author11=Lawrence Wilkinson |name-list-style=amp |date=2005 |title=Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice |journal=Nature Genetics |volume=37 |issue=6 |pages=625–629 |doi=10.1038/ng1577 |pmid=15908950 |s2cid=30560392}}{{cite journal |author=Raefski, A.S. |author2=O'Neill, M. J. |name-list-style=amp |date=2005 |title=Identification of a cluster of X-linked imprinted genes in mice |journal=Nat. Genet. |volume=37 |issue=6 |pages=620–624 |doi=10.1038/ng1567 |pmid=15908953 |s2cid=22141422}} Further studies are aimed at discovering whether these genes contribute directly to behavior and whether the counterpart genes in humans are imprinted.

Epigenetic alterations of the methylation states of genes such as MECP2 and EGR2 have been shown to play a role in autism. MECP2 anomalies have been shown to lead to a wide range of phenotypic variability and molecular complexities.{{cite journal |last1=Percy |first1=Alan K. |date=1 August 2011 |title=Rett Syndrome: Exploring the Autism Link |journal=Archives of Neurology |volume=68 |issue=8 |pages=985–9 |doi=10.1001/archneurol.2011.149 |pmc=3674963 |pmid=21825235}} These variabilities have led to the exploration of the clinical and molecular convergence between Rett syndrome and autism.

Sleeping and language impairments, seizures, and developmental timing are common in both autism and Rett syndrome (RTT). Because of these phenotypic similarities, there has been research into the specific genetic similarities between these two neurodevelopmental conditions. MECP2 has been identified as the predominant gene involved in RTT. It has also been shown that the regulation of the MECP2 gene expression has been implicated in autism.{{cite journal |author=Samaco RC |author2=Nagarajan RP |author3=Braunschweig D |author4=LaSalle JM |date=2004 |title=Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders |journal=Human Molecular Genetics |volume=13 |issue=6 |pages=629–639 |doi=10.1093/hmg/ddh063 |pmid=14734626 |doi-access=free}} Rett syndrome brain samples and autism brain samples show immaturity of dendrite spines and reduction of cell-body size due to errors in coupled regulation between MECP2 and EGR2.{{cite journal |author=Armstrong D |author2=Dunn JK |author3=Antalffy B |author4=Trivedi R |date=1995 |title=Selective dendritic alterations in the cortex of Rett syndrome |journal=J Neuropathol Exp Neurol |volume=54 |issue=2 |pages=195–201 |doi=10.1097/00005072-199503000-00006 |pmid=7876888 |s2cid=19510477}} However, because of the multigene involvement in autism, the MECP2 gene has only been identified as a vulnerability factor in autism.{{cite journal |author=Shahbazian, M.D. |author2=Zoghbi, H.Y. |date=2002 |title=Rett Syndrome and MeCP2: Linking Epigenetics and Neuronal Function |journal=American Journal of Human Genetics |volume=71 |issue=6 |pages=1259–1272 |doi=10.1086/345360 |pmc=378559 |pmid=12442230}} The most current model illustrating MECP2 is known as the transcriptional activator model.

Another potential molecular convergence involves the early growth response gene-2 (EGR2). EGR2 is the only gene in the EGR family that is restricted to the central nervous system and is involved in cerebral development and synaptic plasticity. EGR2 expression has been shown to decrease in the cortexes of individuals with both autism and RTT.{{cite journal |author=Swanberg SE |author2=Nagarajan RP |author3=Peddada S |author4=Yasui DH |author5=LaSalle JM |date=2009 |title=Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism |journal=Human Molecular Genetics |volume=18 |issue=3 |pages=525–534 |doi=10.1093/hmg/ddn380 |pmc=2638799 |pmid=19000991}} MECP2 expression has also been shown to decrease in individuals with RTT and autism. MECP2 and EGR2 have been shown to regulate each other during neuronal maturation. A role for the dysregulation of the activity-dependent EGR2/MECP2 pathway in RTT and autism has been proposed. Further molecular linkages are being examined; however, the exploration of MECP2 and EGR2 have provided a common link between RTT, autism, and similarities in phenotypic expression.

Folate pathways have been studied to be potential predictors of autism. A few genetic polymorphisms such as folate hydrolase 1 and hydroxymethyltransferase 1 along with hyperhomocysteinemia were used as factors contributing to autism to develop an artificial neural network (ANN). Studies showed that this model was around 63.8% accurate in predicting autism likelihood, implying a moderate association between genetic polymorphisms of the folate pathway and autism likelihood.

*8*

The most important methyl donor for DNA methylation is 5-methyl-tetrahydrofolate. Consequently, any changes in folate levels or folate metabolism could significantly impact DNA methylation and contribute to what causes autism. This idea is what makes folate pathways a potential predictor of autism because genetic polymorphisms of the folate pathway could have different effects on DNA methylation. In general, lower folate levels in pregnant women have been associated with increased autism likelihood. The effect of enhancing folate levels on the features of autism are still being researched and have yet to be confirmed.{{Cite journal |last1=Waye |first1=Mary M. Y. |last2=Cheng |first2=Ho Yu |date=2018 |title=Genetics and epigenetics of autism: A Review: Genetics and epigenetics of autism |journal=Psychiatry and Clinical Neurosciences |language=en |volume=72 |issue=4 |pages=228–244 |doi=10.1111/pcn.12606|pmid=28941239 |s2cid=206257210 |doi-access=free }}

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Category:Epigenetics

Category:Genetics of autism