GIGYF1 disruption associates with autism and impaired IGF-1R signaling.

Researchers found that mutations in a gene called GIGYF1 are strongly linked to autism. Children with autism who have these GIGYF1 mutations tend to have fewer learning difficulties compared to children with mutations in other autism genes. Studies in mice showed that losing this gene causes social problems but not necessarily thinking problems. The gene helps brain cells use important growth signals properly during brain development.

This study identified GIGYF1 as the second-most mutated gene among known high-confidence autism risk genes. Researchers analyzed 46 likely gene-disruptive variants in GIGYF1, finding inherited variants were 1.8 times more common than de novo mutations. Individuals with autism and GIGYF1 mutations showed less cognitive impairment compared to those with other high-confidence gene mutations. Mouse studies revealed that partial GIGYF1 loss caused social impairments without cognitive deficits, while complete loss caused both social and cognitive problems.

The mechanism involves GIGYF1's role in regulating IGF-1R receptor recycling; its loss disrupts IGF-1R/ERK signaling and reduces upper-layer cortical neurons during development.

GIGYF1 mutations may represent a distinct autism subtype with preserved cognitive abilities. This could inform precision medicine approaches and help clinicians provide more accurate prognosis. The IGF-1R signaling pathway represents a potential therapeutic target for individuals with GIGYF1-related autism.

Sample size not reported. Study combines genetic analysis with mouse models, which may not fully translate to human autism presentations. The specific clinical assessments used to measure cognitive impairment are not detailed in the abstract.

Autism spectrum disorder (ASD) represents a group of neurodevelopmental phenotypes with a strong genetic component. An excess of likely gene-disruptive (LGD) mutations in GIGYF1 was implicated in ASD. Here, we report that GIGYF1 is the second-most mutated gene among known ASD high-confidence risk genes. We investigated the inheritance of 46 GIGYF1 LGD variants, including the highly recurrent mutation c.333del:p.L111Rfs*234.

Inherited GIGYF1 heterozygous LGD variants were 1.8 times more common than de novo mutations. Among individuals with ASD, cognitive impairments were less likely in those with GIGYF1 LGD variants relative to those with other high-confidence gene mutations. Using a Gigyf1 conditional KO mouse model, we showed that haploinsufficiency in the developing brain led to social impairments without significant cognitive impairments. In contrast, homozygous mice showed more severe social disability as well as cognitive impairments.

Gigyf1 deficiency in mice led to a reduction in the number of upper-layer cortical neurons, accompanied by a decrease in proliferation and increase in differentiation of neural progenitor cells. We showed that GIGYF1 regulated the recycling of IGF-1R to the cell surface. KO of GIGYF1 led to a decreased level of IGF-1R on the cell surface, disrupting the IGF-1R/ERK signaling pathway. In summary, our findings show that GIGYF1 is a regulator of IGF-1R recycling.

Haploinsufficiency of GIGYF1 was associated with autistic behavior, likely through interference with IGF-1R/ERK signaling pathway.