Autism's genetic code: Scientists uncover two distinct paths to diagnosis
By willowt // 2025-11-10
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  • Autism has a strong genetic basis, driven by both rare, high-impact mutations and common, inherited gene variations.
  • A single gene, SHANK3, can cause vastly different outcomes—from no autism to profound autism—depending on the number of copies a person has.
  • Genetic research is paving the way for targeted treatments for severe, "profound" autism, including nutrient supplementation and gene-activating therapies.
  • Genes are estimated to account for about 60% of autism risk, indicating environmental factors also play a significant role.
  • The sharp rise in autism prevalence, especially in severe cases, suggests non-genetic factors are contributing to the increase.
In a quiet household, three siblings shared the same parents and environment, yet their lives diverged dramatically due to a single gene. One brother developed mild autism, his sister profound autism with an intellectual disability, and the other brother developed typically. This real-world case, studied by French researchers, underscores the powerful and complex role genetics plays in autism spectrum disorder (ASD), a condition affecting an estimated 1 in 36 children. As scientists piece together the autism puzzle, they are discovering that our DNA holds not only clues to its causes but also the potential for future, targeted treatments for its most severe forms.

Two Primary Genetic Pathways

Research led by institutions like the Autism Sequencing Consortium has identified two main genetic drivers of autism. The first involves rare, spontaneous mutations known as de novo mutations. These are new genetic changes not inherited from either parent and often have a strong effect. A single de novo mutation can be enough to cause autism, frequently accompanied by more significant challenges like intellectual disability. The second, and more common, pathway involves polygenic variations. This refers to the combined effect of hundreds or even thousands of common gene variants inherited from both parents. Individually, each variant's impact is tiny, but collectively they can significantly increase autism risk. Joseph Buxbaum, director of the Seaver Autism Center, compares it to height: a person can inherit common variants for short stature but still be tall based on their overall genetic makeup. This complexity explains why autism can sometimes appear to skip generations or vary widely in its presentation.

The SHANK3 Gene: A Case Study in Complexity

The story of the three siblings hinges on the SHANK3 gene, which helps form proteins critical for communication between brain cells. Located on chromosome 22, the number of functional SHANK3 copies each child had dictated their neurodevelopmental outcome. The typically developing brother had the standard two copies. The brother with Asperger’s had an extra piece of the chromosome, giving him three copies. The sister with severe autism had a missing piece, leaving her with only one functional copy. This case illustrates how specific genes can directly influence brain circuitry. Over 100 genes have been strongly linked to autism, many of which, like SHANK3, are involved in brain cell formation, maturation, and communication. Other genes work more indirectly; for example, the genetic condition phenylketonuria can lead to toxic brain levels of an amino acid, triggering autism-like symptoms if not managed through diet.

From Cause to Potential Treatment

For individuals with severe, or "profound," autism linked to a known genetic cause, research is opening doors to previously unthinkable interventions. "When we look at individuals with autism and a significant cognitive impairment, the likelihood of identifying the underlying cause... is around 30 to 35 percent," said Dr. Christian Schaaf, a medical geneticist at Heidelberg University. These discoveries are leading to innovative treatment strategies. Rather than attempting risky gene editing, some approaches focus on compensating for the faulty gene. If a child has one healthy gene copy, therapies can aim to boost its activity. Alternatively, if a genetic defect causes a nutrient deficiency, supplementation can help. Dr. Schaaf’s team successfully halted developmental regression in a young boy with a TMLHE gene mutation by supplementing with carnitine, the nutrient his body could not produce. Promising clinical trials are also underway for related conditions. Research into Angelman syndrome, often linked with autism, involves turning on a dormant paternal copy of a gene, with preliminary results showing improvements in cognition and language. Similar trials for Fragile X syndrome have shown that raising levels of a key brain signaling molecule can improve cognition in adults.

A Puzzle with Missing Pieces

Despite the progress, genetics alone does not tell the full story. Current estimates suggest genes account for approximately 60% of autism risk. The dramatic rise in prevalence—from about 0.06% in the 1980s to over 3% today—cannot be explained by genetics alone, as gene frequencies in the population do not change that quickly. Even studies on identical twins, who share nearly identical DNA, show that in about 10% of pairs, one twin has autism while the other does not, pointing to the influence of non-genetic factors. "The assumption in twin studies is that the amount of environmental sharing between identical and fraternal twins is the same, which may not be the case," said Neil Risch, a geneticist at the University of California–San Francisco. Differences in prenatal exposure to nutrients, toxins, or other factors could play a role. The sharp increase in profound autism cases, which rose about 70% from 2000 to 2016 according to CDC data, further suggests that environmental influences are a critical piece of the puzzle yet to be fully understood.

Navigating a New Genetic Frontier

The journey to understand autism is akin to the parable of the blind men and the elephant—each research focus reveals a different part of the whole. The genetic landscape of autism is vast, encompassing both powerful single-gene mutations and the subtle, cumulative effects of thousands of common variants. For families facing the challenges of profound autism, this research brings a beacon of hope, offering a path toward treatments that could alleviate the most disabling symptoms. Yet, the steadily rising prevalence signals that the complete picture must also include environmental factors and developmental biology. As science continues to decode the complex interplay between our genes and our environment, the goal remains a fuller understanding of autism that leads to better support and outcomes for all individuals on the spectrum. Sources for this article include: TheEpochTimes.com Nature.com PubMed.com BBC.com      
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