Autism Study Reveals New Genetic Players and Role of Language Delay – Neuroscience News

Summary: Researchers are shedding new light on how genetics may influence the development of autism spectrum disorder (ASD).

The study, the largest ever to target families with multiple children diagnosed with autism, has identified a possible risk gene. In addition, it provided genetic evidence to reconsider language delay as a primary cause of autism.

These findings highlight the complex interaction between common and rare genetic variants in determining the risk of autism.

Key facts:

1. UCLA health researchers conducted the largest study to date of families with one child diagnosed with autism, revealing seven risk genes.
2. The study highlights the importance of the role of both common and rare genetic variants in the risk of autism.
3. Genetic evidence from the study suggests that language delays and dysfunctions may be the primary cause of autism, contrary to the DSM-5 diagnostic guidelines.

Source: UCLA

UCLA Health researchers have published the largest study ever of families with at least two children with autism, discovering new risk genes and providing new insights into how genetics affects whether a person develops autism spectrum disorder.

A new study, published in the Proceedings of the National Institute of Scienceit also provides genetic evidence that language delay and dysfunction should be reconsidered as a primary component of autism.

Most autism genetic studies focus on families with one child affected by the neurodevelopmental disorder, sometimes excluding families with multiple affected children.

As a result, few studies have examined the role of rare inherited variants or their interaction with the combined effect of common genetic variants that contribute to the risk of developing autism.

“Study design is very important and not enough attention has been paid to studying families with one affected child,” said lead 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 genetic risk is attributable to common genetic mutations and another 15%-20% is due to spontaneous mutations or predictable inheritance patterns. The remaining genetic risk has not been determined.

In this study, researchers sequenced the whole genome of 4,551 individuals from 1,004 families with at least two children diagnosed with autism. This group included 1,836 children with autism and 418 children without a diagnosis of autism.

The researchers found seven genes predicted to increase the risk of autism: PLEKHA8, PRR25, FBXL13, VPS54, SLFN5, SNCAIP, and TGM1.

This is noteworthy because other studies have had to analyze much larger groups to identify the same number of risk factors. This is because in this case, most of the new genes were supported by rare DNA mutations that were passed down from parents to children with autism.

The researchers also examined polygenic risk, where a combination of common genetic variants can raise the likelihood of developing autism. They found children who inherit rare mutations from unaffected parents are associated with polygenic risk more likely to develop autism.

This helps explain why parents who carry a rare mutation may not show symptoms of autism even if their children do. It also provides support for the liability threshold model, a behavioral genetics hypothesis that holds that there is an additive genetic effect that influences the likelihood that an individual will develop a particular trait.

In another important result, children with language delay had a higher probability of having polygenic scores associated with autism, while there was no similar relationship for children without language delay.

This pattern was specific to autism and was not seen in other symptoms such as educational attainment, schizophrenia or mental disorders, suggesting that there is a link between the genetic risk of autism and language delay.

However, the latest edition of the manual used by mental health providers to diagnose the disorder—the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)—does not consider language delay a core feature of autism, explaining that language ability varies between individuals. with autism.

“This stronger overall risk association for autism in those with language delays suggests that language is a key factor in autism. This finding should be replicated in larger groups, especially those recently recruited under DSM-5,” ​​said Geschwind.

About this autism and genetic research news

Author: Daniel Geschwind
Source: UCLA
Contact: Daniel Geschwind – UCLA
Image: Image attributed to Neuroscience News

Original Research: Open access.
“Rare and polygenic risk factors for ASD in multiple families” by Daniel Geschwind et al. PNAS

Abstract

Contributions of rare risk and polygenic risk to ASD in multiple families

Autism spectrum disorder (ASD) has a complex genetic makeup that includes contributions from de novo and inherited variants. Few studies have been designed to address the role of rare inherited variants or their interaction with common polygenic risk in ASD.

Here, we performed genome-wide sequencing of the largest multifamily cohort to date, including 4,551 individuals in 1,004 families with two or more autistic children.

Using this study design, we identify seven previously undetected ASD genes supported by the majority of rare inherited pathways, finding support for a total of 74 genes in our cohort and 152 in total after pooled analysis with other studies. Children with autism from multiple families show an increased burden of rare inherited protein-truncating variants in known ASD risk genes.

We also find that the ASD polygenic score (PGS) is highly transmitted from nonautistic parents to autistic children who also have rare inherited variants, consistent with combined effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also note that in addition to social dysfunction, language delay is associated with ASD PGS overrepresentation.

These findings are consistent with a genetic risk construct for autism that includes both rare and common mutations and suggest that language delay is a key factor in the biology of autism.