top of page

Genetics and Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that has been growing in prevalence. It’s estimated to affect 1 in 44 children in the U.S, which is a vast increase compared to 1 in 2,000 children in the 1980s (MedlinePlus, 2021). Several causative factors have been explored in this disorder, including environmental exposures, parental age at conception, pregnancy complications, and genetics. Genetics are estimated to contribute 40-80% of ASD risk (MedlinePlus, 2021). Recently, 174 genes have been identified as having “high confidence” in association with autism spectrum disorders (Kruth et al., 2020). In this post, we will be exploring several genetic variants, as well as, candidate genes and their potential impact on ASD. We will also explore genes shared between ASD and common co-occurring conditions, such as seizures.


The gamma-aminobutyric acid type A receptor subunit beta3 (GABRB3) gene encodes a member of the ligand-gated ionic channel family (NCBI, 2022). It is one of the subunits of a multi-subunit chloride channel that serves as the receptor for GABA, which is the main inhibitory neurotransmitter of the brain (Chen et al., 2014). Genetic variants of this gene have been associated with the pathogenesis of ASD and epilepsy (NCBI, 2022). Evidence shows that GABRB3 variants alter the GABAergic signaling pathway in ASD patients. The reduced expression of GABA-alpha receptor subunits including GABRB3 and the GABA synthesizing enzymes, glutamic acid decarboxylase (GAD) 65 and 67 were found in several brain regions of ASD patients (Chen et al., 2014). Three SNPs that may be associated with ASD include rs4906902 T>C, rs8179184 G>A, and rs20317 C>G (Chen et al., 2014).


The SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene is involved in providing instructions for encoding shank proteins which are found in abundance in the brain. These proteins play a role in the functioning of synapses where they act as a scaffold that supports the connection between neurons. The SHANK3 protein is also involved in the formation and maturation of dendritic spines (MedlinePlus, 2021). There are 67 pathogenic variants with several of these SNPs being identified in autistic patients (dbSNP, n.d.). Many of these SNPs disrupt the functionality of SHANK3 protein or prevent its formation. As it relates to ASD, it’s been postulated that the disruption in communication between neurons contributes to the clinical presentation of ASD (MedlinePlus, 2021).


The SH3 And Multiple Ankyrin Repeat Domains 2 (SHANK2) gene is a postsynaptic density protein that is located at excitatory glutamatergic synapses (Vyas et al., 2021). It is involved in synapse development, where it interacts with other postsynaptic density proteins to regulate surface glutamate receptors and the actin cytoskeleton (Vyas et al., 2021). Similar to the SHANK3 gene, it is highly sensitive to zinc which points to zinc supplementation as a potential therapeutic target. There are four pathogenic variants of the SHANK2 gene with the rs1565527302 TG>- variant being associated with ASD (dbSNP, n.d.).


The potassium voltage-gated channel subfamily Q member 3 (KCNQ3) gene provides instructions for potassium channels and supports the transport of potassium ions into and out of cells (MedlinePlus, 2011). These channels are highly active in the brain as they transmit M-currents which inhibit neurons from continuously signaling other neurons, or in other words, prevents over-excitability of neurons (MedlinePlus, 2011). There are 21 pathogenic variants associated with the KCNQ3 gene, most of which are related to seizures. Examples of these variants include rs118192247 C>T, rs118192248 T>A,C, and rs118192249 A>G (dbSNP, n.d.). Gain-of-function KCNQ3 variants are associated with neurodevelopmental disability, neonatal epilepsy, and ASD (Sands et al., 2019).


The ankyrin 2 (ANK2) gene provides instructions for making a protein called ankyrin-B (MedlinePlus, 2017). Ankyrin-B proteins are primarily located in the brain and heart. In cardiac muscle, this protein interacts with ion channels and ion transporters to generate the electrical signals that control the heartbeat and maintain a normal heart rhythm (Medline Plus, 2017). ANK2 is highly expressed in the early neurodevelopmental stages. Pathogenic variants of the ANK2 gene that may inhibit its expression and thus interfere with neural development include rs72544141 A>G, rs121912706 C>T, rs757033443 C>A,T, rs768327292 C>T, rs2092061253 C>T (dbSNP, n.d.). ANK2 haploinsufficiency may present an increased risk factor for ASD due to decreased neurogenesis in the cerebral cortex (Kawano et al., 2022).


The calcium voltage-gated channel subunit alpha1 H (CACNA1H) gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex (NIH, 2022). This gene influences the influx of calcium ions into the cell upon membrane polarization and consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit forms the pore through which calcium ions pass into the cell. The CACNA1H gene has four pathogenic variants for ASD including, rs28365117, rs370675810, rs372453886, and rs757713867 (Viggiano et al., 2022). Genes involved in voltage-gated calcium channels, including CACNA1H, have been implicated as high-confidence susceptibility genes for ASD, due to the relevant role of calcium signaling in neuronal function (Viggiano et al., 2022). Pathogenic variants for this gene have also been linked to hyperaldosteronism (Danii et al., 2016).


The pogo transposable element derived with ZNF domain (POGZ) gene provides instructions for the POGZ protein that’s found in the cell nucleus and is a part of the zinc finger proteins (MedlinePlus, 2018). The regions of the zinc finger domains consist of amino acids and zinc ions. POGZ protein attaches to chromatin and determines how tightly DNA is packaged. This mechanism determines how the gene is expressed. There are 55 pathogenic POGZ variants with rs142133690 G>A,C being associated with neurodevelopmental disorders (dbSNP, n.d.). In ASD, alterations to chromatin remodeling result in alterations to gene expression and may lead to altered brain development such as impaired cortical development (Matsumura et al., 2020). This can cause the intellectual disability known as White-Sutton syndrome which is more prevalent in the ASD population compared to the general population (Assia et al., 2019).


The sodium voltage-gated channel alpha subunit 2 (SCN2A) gene has 146 pathogenic variants with some variants being associated with seizure disorders and ASD (dbSNP, n.d.). A few examples of pathogenic variants include rs121917748 C>T, rs121917749 C>T, and rs121917750 C>G which are associated with epilepsy and possibly ASD (dbSNP, n.d.). Voltage-gated sodium channels are involved in the function of action potentials in neurons and muscle (MedlinePlus, 2021). A small subset of autism cases has been directly tied to a single causal mutation, such as loss-of-function mutations in SCN2A which cause SCN2A syndrome (Kruth et al., 2020). SCN2A encodes the voltage-gated sodium channel NaV1.2, which is of interest in the ASD population because of the implications dependent on the phenotype. For example, the gain-of-function is associated with epilepsy, whereas the loss-of-function mutation is associated with the subset of ASD with an intellectual disability (Kruth et al., 2020).


The trimethyllysine hydroxylase, epsilon (TMLHE) gene encodes the protein trimethyllysine dioxygenase which is the first enzyme in the carnitine biosynthesis pathway (NCBI, 2022). Carnitine is essential for the transport of activated fatty acids across the inner mitochondrial membrane. There are 3 pathogenic variants of the TMLHE gene, with one of the variants, rs782624357 deletion AT, being clinically significant for ASD (dbSNP, n.d.). A study by Celestino-Soper et al., (2012) found that TMLHE deficiency caused by deletion of exon 2 was shown to be 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls.


The acetylserotonin O-methyltransferase (ASMT) gene is involved in the final reaction in the synthesis of melatonin, converting serotonin to melatonin, and is found abundantly in the pineal gland (NIH, 2022). This gene is of interest to ASD patients because sleep disturbances are commonly observed in individuals with ASD, with prevalence estimates ranging from 50 to 80 % (Veatch et al., 2015). Variants of the ASMT gene that are associated with sleep disturbances in ASD patients include rs4446909 G>A,T, rs5989681 G>A,C, and rs6644635 T>A,C (Veatch et al., 2015). These SNPs are associated with reduced expression of ASMT, thus inhibiting the functional production of melatonin.


In summary, many of these genetic variants will present in ASD patients independently. As one can see, there are several pathogenic variants that are shared between ASD and common co-occurring conditions such as epilepsy. While there isn’t a one-size approach to nutrition and medication recommendations for this population, a few broad similarities stood out for these particular genetic variants. The ketogenic diet, or a variation of the diet shows promise in addressing the neuronal overexcitability, particularly in the presence of epilepsy. Zinc is another nutrient that showed evidence in improving neurological function based on its beneficial mechanisms on synapse function. Important nutrients to monitor as it relates to cases of epilepsy in ASD patients are sodium and potassium. Carnitine may provide a nutritional target in the prevention of episodes of autism regression. Vitamin B6 may be beneficial for carriers of the GABRB3 variants. Lastly, melatonin may be a beneficial supplemental therapy to improve sleep-related issues in the ASD population.

In a future post, we will explore SNPs involved in methylation and transsulfuration.


ANK2 gene: MedlinePlus Genetics. (2017). Retrieved 30 July 2022, from

ASMT acetylserotonin O-methyltransferase - Gene - NCBI. (2022). Retrieved 28 July 2022, from

Assia Batzir N, Posey JE, Song X, Akdemir ZC, Rosenfeld JA, Brown CW, Chen E, Holtrop SG, Mizerik E, Nieto Moreno M, Payne K, Raas-Rothschild A, Scott R, Vernon HJ, Zadeh N; Baylor-Hopkins Center for Mendelian Genomics, Lupski JR, Sutton VR. Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome). Am J Med Genet A. 2020 Jan;182(1):38-52. doi: 10.1002/ajmg.a.61380. Epub 2019 Nov 29. PMID: 31782611; PMCID: PMC7713511.

Autism spectrum disorder: MedlinePlus Genetics. (2021). Retrieved 6 July 2022, from

CACNA1H calcium voltage-gated channel subunit alpha1 H [Homo sapiens (human)] - Gene - NCBI. (2022). Retrieved 12 July 2022, from

Chen CH, Huang CC, Cheng MC, Chiu YN, Tsai WC, Wu YY, Liu SK, Gau SS. Genetic analysis of GABRB3 as a candidate gene of autism spectrum disorders. Mol Autism. 2014 Jun 25;5:36. doi: 10.1186/2040-2392-5-36. PMID: 24999380; PMCID: PMC4082499.

Celestino-Soper, P., Violante, S., Crawford, E., Luo, R., Lionel, A., & Delaby, E. et al. (2012). A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proceedings Of The National Academy Of Sciences, 109(21), 7974-7981. doi: 10.1073/pnas.1120210109

Daniil G, Fernandes-Rosa FL, Chemin J, Blesneac I, Beltrand J, Polak M, Jeunemaitre X, Boulkroun S, Amar L, Strom TM, Lory P, Zennaro MC. CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism. EBioMedicine. 2016 Nov;13:225-236. doi: 10.1016/j.ebiom.2016.10.002. Epub 2016 Oct 4. PMID: 27729216; PMCID: PMC5264314.

GABRB3 gamma-aminobutyric acid type A receptor subunit beta3 [Homo sapiens (human)] - Gene - NCBI. (2022). Retrieved 16 July 2022, from

Gene: TMLHE -. (2022). Retrieved 26 July 2022, from

Kawano, S., Baba, M., Fukushima, H., Miura, D., Hashimoto, H., & Nakazawa, T. (2022). Autism-associated ANK2 regulates embryonic neurodevelopment. Biochemical And Biophysical Research Communications, 605, 45-50. doi: 10.1016/j.bbrc.2022.03.058

KCNQ3 gene: MedlinePlus Genetics. (2011). Retrieved 30 July 2022, from

Kruth KA, Grisolano TM, Ahern CA, Williams AJ. SCN2A channelopathies in the autism spectrum of neuropsychiatric disorders: a role for pluripotent stem cells? Mol Autism. 2020 Apr 7;11(1):23. doi: 10.1186/s13229-020-00330-9. PMID: 32264956; PMCID: PMC7140374.

Matsumura, K., Seiriki, K., Okada, S. et al. Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes. Nat Commun 11, 859 (2020).

POGZ gene: MedlinePlus Genetics. (2018). Retrieved 30 July 2022, from

Sands TT, Miceli F, Lesca G, Beck AE, Sadleir LG, Arrington DK, Schönewolf-Greulich B, Moutton S, Lauritano A, Nappi P, Soldovieri MV, Scheffer IE, Mefford HC, Stong N, Heinzen EL, Goldstein DB, Perez AG, Kossoff EH, Stocco A, Sullivan JA, Shashi V, Gerard B, Francannet C, Bisgaard AM, Tümer Z, Willems M, Rivier F, Vitobello A, Thakkar K, Rajan DS, Barkovich AJ, Weckhuysen S, Cooper EC, Taglialatela M, Cilio MR. Autism and developmental disability caused by KCNQ3 gain-of-function variants. Ann Neurol. 2019 Aug;86(2):181-192. doi: 10.1002/ana.25522. Epub 2019 Jun 26. PMID: 31177578.

TMLHE trimethyllysine hydroxylase, epsilon [Homo sapiens (human)] - Gene - NCBI. (2022). Retrieved 25 July 2022, from

Veatch OJ, Pendergast JS, Allen MJ, Leu RM, Johnson CH, Elsea SH, Malow BA. Genetic variation in melatonin pathway enzymes in children with autism spectrum disorder and comorbid sleep onset delay. J Autism Dev Disord. 2015 Jan;45(1):100-10. doi: 10.1007/s10803-014-2197-4. PMID: 25059483; PMCID: PMC4289108.

Viggiano M, D'Andrea T, Cameli C, Posar A, Visconti P, Scaduto MC, Colucci R, Rochat MJ, Ceroni F, Milazzo G, Fucile S, Maestrini E, Bacchelli E. Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility. Front Psychiatry. 2022 Mar 8;13:858238. doi: 10.3389/fpsyt.2022.858238. PMID: 35350424; PMCID: PMC8957782.

Vyas Y, Jung Y, Lee K, Garner CC, Montgomery JM. In vitro zinc supplementation alters synaptic deficits caused by autism spectrum disorder-associated Shank2 point mutations in hippocampal neurons. Mol Brain. 2021 Jun 24;14(1):95. doi: 10.1186/s13041-021-00809-3. PMID: 34167580; PMCID: PMC8223320.

13 views0 comments


bottom of page