UCLA Health researchers have published the largest-ever study of families with at least two children with autism, uncovering new risk genes and providing new insights into how genetics influence the development of autism.
The new study, published on July 28 in the Proceedings of the National Academy of Sciences, also provides genetic evidence that language delay and dysfunction should be reconsidered as a core component of autism.
The majority of genetic studies on autism have concentrated on families with a single affected child, often excluding families with multiple affected children. Consequently, very few studies have explored the impact of rare inherited genetic variations or their interaction with the collective effect of multiple common genetic variations that contribute to the risk of developing autism.
“Study design is critical, and not enough attention has been paid to studying families with more than one affected child,” said lead study author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology, and Psychiatry at UCLA.
“Autism is highly heritable. It is estimated that at least 50% of the genetic risk is attributed to common genetic variations, while another 15-20% is due to spontaneous mutations or predictable inheritance patterns. The remaining genetic risk is still not completely understood.”
For this study, researchers conducted whole-genome sequencing on 4,551 individuals from 1,004 families, including 1,836 children with autism and 418 without.
The researchers found seven potential genes linked to autism: PLEKHA8, PRR25, FBXL13, VPS54, SLFN5, SNCAIP, and TGM1. This is notable because previous studies needed larger cohorts to find a similar number of new risk genes. Most of the new genes were supported by rare inherited DNA variations passed from parents to children with autism.
The researchers also looked into polygenic risk, which involves a combination of commonly found genetic variations that can increase the likelihood of developing autism. They discovered that children who inherit rare mutations from unaffected parents, combined with polygenic risk, are more likely to have autism. This helps to explain why parents who have a single rare mutation may not display signs of autism, even if their children do. It also supports the liability threshold model, a concept in behavioral genetics that suggests there is an additive effect of genes influencing the probability of developing a certain trait.
Children who experienced language delay were more likely to inherit a polygenic score linked to autism, compared to children without language delays. This association was specific to autism and was not observed for other traits such as educational attainment, schizophrenia, or bipolar disorder. This suggests a connection between the genetic predisposition for autism and language delay.
The most recent edition of the professional guidebook used by mental health providers to diagnose disorders, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), does not consider language delay a core symptom of autism. This is due to the variability in language ability among people with autism.
“This association of general risk for autism that was strongest in those with language delay suggests that language is actually a core component of autism. This finding needs to be replicated in larger cohorts, especially those recruited more recently under DSM-5,” Geschwind said.