Study Reveals Impact of Genetic Mutations Beyond Autism Diagnosis

Over 180 genes have been identified as contributing to autism spectrum disorders (ASD). Historically, however, researchers have focused more on diagnosing disease rather than understanding the range of phenotypes expressed by these gene interactions.

In a recent study published in natural medicine, Scientists conducted the largest meta-analysis to phenotype individuals diagnosed with ASD and previously understudied undiagnosed patients.

study: Phenotypic effects of genetic variants associated with autism. Image credit: SewCreamStudio/Shutterstock.com

Background

This study reveals the direct impact of genetics on ASD diagnosis and the impact of social, economic, and environmental context on externally observable behaviors of individuals on the ASD spectrum.

“Autism” is short for “autism spectrum disorder (ASD),” a complex neurological and developmental condition that impairs an individual’s social interactions, communication, intelligence, and behavior. The World Health Organization (WHO) estimates that 10% of the world’s population suffers from autism.

The phenotypic expression of ASD is unique to each individual, and there is a rapidly growing body of literature investigating the gene-environment interactions that shape these expressions. Despite decades of research into the genotypic basis of ASD and other neurodevelopmental disorders (NDDs), most studies have focused on diagnosed patients.

Undiagnosed individuals remain largely ignored, even if they carry one or more of the same loss-of-function (LoF) gene alleles found in ASD patients.

This indicates a gap in our understanding of the inter-individual phenotypic variability of members of the ASD spectrum and its impact on the socioeconomic status of many undiagnosed people.

About research

In this study, the researchers sought to elucidate the relative contributions of genes present in ASD patients and to cognitive impairment in undiagnosed individuals of common European ancestry within the framework of a meta-analysis. studies were reviewed.

They first collected 226,649 whole exome sequences (WES), including 13,091 diagnosed ASD patients, their 19,488 relatives, and 194,070 other undiagnosed patients.

185 autosomal genes were selected based on having LoF mutant alleles with confirmed association with NDD.

Subsequently, we collected and edited a set of 2,492 genes with no direct NDD association, but the study concluded that these genes were ‘intolerant’ to ASD LoF variants. Intolerant genes are genes in which protein truncation variants (PTVs) or other mutations are absent or remain at very low frequency. That is, they are either actively eliminated by natural selection or selected for their survival within the population.

The relationship between autism and biological function was analyzed by assessing gene expression levels across four different regions of the brain and eight different periods of fetal development.

Genome-wide association studies (GWAS)-based diagnosis of autism has been evaluated using the polygenic score (PGS) to assess whether genetic makeup can accurately predict the presence and intensity of ASD in previously undiagnosed humans. ) were summarized simultaneously to arrive at .

Phenotypic cognitive information in the form of social and communicative questionnaires (SCQ), intelligence quotients (IQ), and indices of repetitive behavior, social interaction, communication difficulties, and self-harm behavior was compiled for participants. I was.

This was done to establish a conventional diagnostic cutoff in a nearly continuous spectrum from non-ASD to severe ASD propensity.

Finally, to test previous claims that some genes associated with autism can alter brain anatomy, we examined 21,040 individuals from the UK Biobank, including 1,675 with ASD. ) magnetic resonance imaging (MRI) was analyzed.

research result

Corroborating previous studies, all 185 selected LoF genes were found in different combinations of individuals diagnosed with ASD, and gene prevalences were consistent with odds ratios (OR). That is, a higher OR corresponded to a wider prevalence in the ASD group.

Of these, 134 LoF genes were found in at least one undiagnosed individual and may represent complex environmental, social and genetic interactions underpinning behavior and diagnosis.

Gene presence and OR in undiagnosed individuals correlated with lower entitlement and income and lower intelligence, all of which were statistically significant, not only in individuals with extreme ASD spectrum, but also in ASD range. It highlights the lack of support provided by society even to those with shallower literacy. Genetics for this condition.

Strikingly, higher PGS scores in people diagnosed with autism are directly related to decreased income, but inversely correlated with fluid intelligence, with people with autism having higher intelligence. .

MRI imaging confirmed the presence of significant alterations in brain anatomy in ASD LoF gene-positive individuals compared to individuals without these mutations, corroborating previous studies and It is backed up.

Conclusion

This study is the largest meta-analysis of autism to date and the first to focus on undiagnosed carriers of autism-related genes. The results show that the presence and OR of ASD genes can predict an individual’s ASD diagnosis.

However, due to social factors and developmental circumstances, carriers (individuals with autism-related genes) may go undiagnosed and live with the economic and cognitive disadvantages of ASD for the rest of their lives.

Gender has been identified as a confounding factor for some genes, and mothers were found to transmit some LoF genes more than fathers. Although the gene load of female and male offspring was found to be nearly identical, the phenotypic expression of autism was preferentially or exclusively in males, which could be attributed to the low OR of rare ASD genes. suggesting that females are intrinsically more tolerant than their male counterparts.

“The social environment also influences whether people with autistic traits are diagnosed. , there is still progress at the social level.”

Finally, this study highlights the need for an educational system tailored to individuals with different needs across the NDD spectrum, which may later serve.

Furthermore, the presence of ASD genes in individuals is often masked in phenotypes, and future studies exploring the biological basis of such multiple gene interactions are needed to improve future diagnosis. Is required.

Such research, combined with data that considers environmental, social, economic and genetic factors, has the potential to benefit humanity as a whole given the further contributions of many talented individuals.