For decades, one question has quietly troubled autism researchers across the world: why are boys diagnosed with autism nearly four times more often than girls?

Now, scientists in South Korea believe they may finally have found the strongest evidence yet that girls are born with a kind of natural biological protection against autism— but that protection is not unbreakable.

In a groundbreaking achievement, a team from KAIST, Yonsei University, and the Institute for Basic Science has created the first living animal model with serious mutations in both copies of the CHD8 gene, which is one of the strongest genetic risk factors for autism.

The findings could reshape how doctors understand autism, ADHD, intellectual disability, and even schizophrenia.

Scientists have long suspected that girls possess hidden biological mechanisms that help shield the developing brain from certain genetic disruptions. But proving it experimentally remained frustratingly difficult.

The CHD8 gene acts almost like a chief architect during early brain development. It helps organise chromatin—the tightly packed structure that controls how thousands of other genes switch on and off in growing brain cells. When CHD8 malfunctions, the effects can spread like a chain reaction across the brain.

Earlier studies involving milder CHD8 mutations showed behavioural problems mainly in male animals, mirroring what doctors see in humans. But researchers hit a dead end whenever they tried creating severe “double-copy” mutations. The embryos simply did not survive long enough to study.

After months of failed breeding attempts, the Korean team used a specialised hybrid genetic background, which finally allowed the fragile embryos to stay alive. For the first time, scientists could watch how severe autism-linked mutations affected both male and female brains in real time.

What they found was striking.

Male mice carrying a single faulty CHD8 copy developed autism-like behavioural changes, while female mice remained relatively protected. But when both copies of the gene were severely damaged, that female resilience collapsed completely.

The researchers observed enlarged brain volume, unstable electrical brain rhythms, disrupted blood flow, and widespread damage to systems responsible for communication between brain cells. Even the mitochondria — the tiny energy factories that power cells — appeared impaired.

In simple terms, the brain’s messaging network began falling into chaos.

“Our findings suggest that females might have some natural protections against problems caused by CHD8 mutations, but very serious mutations can overpower those protections,” said Professor LEE Eunee of Yonsei University.

The study also showed that male-female differences became progressively weaker as the mutation grew more severe, suggesting that biological sex alone does not decide autism vulnerability. The intensity of the genetic disruption matters enormously.

“Through this study using a suitable homozygous CHD8 mutant mouse model, we have thoroughly explained how severe autism develops in the brain and at the genetic level,” said Director KIM Eunjoon of the IBS Center for Synaptic Brain Dysfunctions.

He added, “By proving for the first time that sex differences in autism vary according to mutation strength, we have established an important foundation for the future development of precision therapeutics that account for both biological sex and severity.”

Researchers say the discovery may eventually help scientists design more personalised treatments based not only on symptoms but also on a person’s exact sex and genetic profile.

For families living with autism, the findings may offer something science has struggled to provide for years — a clearer explanation of why some brains appear naturally protected, while others remain far more vulnerable.