Classifying Autism Spectrum Disorder (ASD): The Key to Unlocking Targeting Genetic Therapies

Written by: Teniola Obayomi

Edited by: Farzana Zane, Riya Raina, Shivani Patel, and Janelle Smith

Illustrated by: Elvan Eren

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According to my aunt, my brother’s first word was cheese—a far cry from the usual “mama” or “dada.” When she told us this for the first time, I remember rolling on the floor laughing, my toddler brain dismissing it. I knew that my little brother liked to watch us eat Cheetos, but how could he know cheese better than his parents? 

While we debated the first word that my brother said, we had no clue what his last word was. When he was two, my brother was diagnosed with non-verbal autism spectrum disorder (ASD). Over the course of a few months, his short words and phrases melted into chirps and groans, which are now his main modes of communication. 

After his diagnosis, my brother has learned how to use a text-to-speech iPad program to communicate. For example, when he wants to get McDonald’s fries (his comfort meal), he taps on the appropriate button, and the iPad verbalizes his thoughts. Besides using an iPad, my brother takes medications like methylphenidate (MPH) and guanfacine to manage his symptoms, which make it easier for him to focus in school and stay calm when he experiences sensory overload. 

MPH increases dopamine levels, which boosts patients’ focus and attention [1]. On the other hand, guanfacine activates alpha-2A receptors located in the nervous system [2, 3]. This activation reduces the level of norepinephrine hormone that is released into the brain, leading to improvements in memory and attention [4, 5]. 

Notably, both MPH and guanfacine are ADHD medications, as there is a lack in 

ASD-specific drugs [6]. Additionally, in low-functioning ASD patients like my brother, MPH has a higher likelihood of worsening symptoms [6]. To improve treatment efficacy and minimize side effects, researchers should focus on developing therapies that target ASD-specific pathways and proteins. Recently, a study by Aviya Litman et al. classified ASD into four subgroups based on biological differences [7]. By correlating certain autism phenotypes to underlying biological mechanisms, Litman et al. open the door to specific autism therapies. 

ASD is caused by both genetic inheritance and environmental factors through epigenetics [8]. The genetics of ASD are very complex, with over 800 genes involved [8]. Additionally, autism usually overlaps with other conditions (e.g., ADHD, anxiety, OCD) making ASD genetics and symptoms difficult to isolate [8]. However, after engaging with ASD patients and their non-autistic siblings, Litman et al. were able to classify autism into four distinct subgroups: Social and Behavioral Challenges, Mixed ASD with Developmental Delay, Moderate Challenges, and Broadly Affected [7]. These groupings were organized based on factors like phenotypic differences, genetic differences, and gene activation timing: the period of development when the brain is affected by ASD-related genetic mutations. For example, researchers found more new mutations within the Broadly Affected group, while children in the Mixed ASD group were more likely to inherit rare alleles. Additionally, children in the Social and Behavioral Challenges group had mutations in genes that activate during late childhood development. 

Notably, researchers found that the four groups differed in their execution of molecular pathways, which was tied to varying activity of biological processes. In other words, certain processes occur more frequently in different classes: chromatin organization, DNA repair regulation, and microtubule activity for the Social and Behavioral class, neuronal action potential, membrane depolarization, and reduced regulation of protein depolymerization for the Mixed ASD class, and histone modification and chromatin organization for the Moderate Challenges class. 

These findings suggest that targeting genes, affected pathways, and underlying biological processes related to each subgroup could be the key to developing effective ASD therapies. In fact, other researchers in the past have identified ASD-associated genes like GABBR1 [9]. Acamprosate—a GABBR1 inhibitor—was tested on ASD patients in a clinical trial, and it boosted attention and social relatedness skills in 67% of adolescent patients [9, 10]. By identifying more genetic targets, studies like Litman et al.’s can fuel the development of similar drugs that address the differing symptoms of each ASD subgroup.

The numbers of ASD patients have increased by 300% over the past twenty years, stressing the need for effective treatments [11]. Within the current political landscape, misinformation about autism has been rampant, with many claiming that the rise in autism patients is due to vaccines. In fact, the United States’ Health Secretary Robert F. Kennedy has vowed to “reinvestigate” this falsehood [12]. However, the increase in ASD diagnoses are actually caused by better screening practices, which are now able to recognise subtle phenotypes and accessible to a wider range of patients [11]. Ultimately, ASD can impact anyone, regardless of gender, race, and vaccination status [11]. False rhetoric is not only harmful to patients and their families, but it is counterproductive. Instead of fueling vaccination fears, the government should allocate more funding towards ASD research, helping to improve the lives of patients like my brother.

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References

[1] Gottlieb S. Methylphenidate works by increasing dopamine levels. BMJ. 2001;322(7281):259. doi:10.1136/bmj.322.7281.259

[2] Brown MJ. Sites of action of alpha 2 agonists and antagonists. Am J Cardiol. 1988;61(7):18D-21D. doi:10.1016/0002-9149(88)90459-6

[3] Jahagirdar D, Mahood Q. Guanfacine for autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or oppositional defiance disorder: rapid review. CADTH Rapid Response Reports. Published July 2022. https://www.ncbi.nlm.nih.gov/books/NBK603607/

[4] Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015;62(1):31-39. doi:10.2344/0003-3006-62.1.31

[5] Alamo C, López-Muñoz F, Sánchez-García J. Mechanism of action of guanfacine: a postsynaptic differential approach to the treatment of ADHD. Actas Esp Psiquiatr. 2016;44(3):107-112

[6] Ventura P, de Giambattista C, Spagnoletta L, et al. Methylphenidate in autism spectrum disorder: a long-term follow-up naturalistic study. J Clin Med. 2020;9(8):2566. doi:10.3390/jcm9082566

[7] Litman A, Sauerwald N, Green Snyder L, et al. Decomposition of phenotypic heterogeneity in autism reveals underlying genetic programs. Nat Genet. 2025;57:1611-1619. doi:10.1038/s41588-025-02224-z

[8] Genovese A, Butler MG. The Autism Spectrum: Behavioral, Psychiatric and Genetic Associations. Genes (Basel). 2023;14(3):677. Published 2023 Mar 9. doi:10.3390/genes14030677

[9] Ma DQ, Whitehead PL, Menold MM, et al. Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. Am J Hum Genet. 2005;77(3):377-388. doi:10.1086/433195

[10] Acamprosate—a GABBR1 inhibitor—was tested on ASD patients in a clinical trial, and it boosted attention and social relatedness skills in 67% of adolescent patients (Erikson et al. 2014

[11] Johns Hopkins Bloomberg School of Public Health. Is there an autism epidemic? Published June 6, 2025. https://publichealth.jhu.edu/2025/is-there-an-autism-epidemic

[12] Woolf S, Rosenthal J. RFK Jr. is systematically undermining vaccine science and endangering health. Center for American Progress. Published June 27, 2025. https://www.americanprogress.org/article/rfk-jr-is-systematically-undermining-vaccine-science-and-endangering-health/