Study identifies rare inherited variants that implicate new autism candidate risk genes

Scientists have found a rare class of genetic differences that are transmitted from parents without autism to their children affected with autism and identified that they are most pronounced in “multiplex” families with more than one family member on the spectrum.


Autism. Image Credit: Lightspring/

The outcomes of the research have been published in the journal Nature Genetics in a paper titled “Recent ultra-rare inherited variants implicate new autism candidate risk genes.”

The hunt for the genes involved in autism is done earnestly. The widespread use of technology and lower costs allow the aggregation of thousands of genomes of people with autism and their family members. Understanding the genes involved will enable a better insight into the condition known as autism and might eventually lead to treatments for those who long for it.

The current research garners attention as the majority of autism genes identified to date have been through studies of de novo mutations, genetic differences that first arise in the person with autism but are not present in either of their parents. The results show that scientists are not to assume that the set of autism genes altered by de novo mutations are the same genes as these newly identified inherited rare variants.

Lead author Amy B. Wilfert, Ph.D., from the University of Washington, said that in an analysis of 10,905 people with autism, the scientists discovered and replicated a rare class of genetic variants that are passed (over-transmitted) from parents without autism to children with autism.

While most autism studies focus on de novo mutations, this study focuses on rare inherited mutations, which are often understudied in autism. We find that these variants are individually less damaging than de novo mutations but have the potential to contribute almost as much risk and impact the same molecular pathways, through a distinct set of genes.”

Amy B. Wilfert, PhD, Study Lead Author, University of Washington

These variants, however, are only able to persist in the general population for a few generations before being selected out by evolution,” adds Wilfert.

It is widely understood that de novo mutations cannot and do not explain all of the genetic causes of autism, a phenomenon sometimes referred to as ‘missing heritability’.

Pamela Feliciano, PhD, Scientific Director, Simons Powering Autism Research

The Simons Powering Autism Research (SPARK) Consortium contributed more than 50% of the genetic data analyzed in this study—that includes exomes from 21,331 SPARK participants, where 6,539 of them are individuals with autism spectrum disorder (ASD).

The number of genomes accessible to scientists at this time permits the search for specific categories of genetic changes—like de novo changes and ultra-rare inherited variants, however not all of them. More genomes coming online enables accessibility of larger categories of variants for analysis.

Interestingly, the vast majority of those variants (95%) are not found in genes already known to be autism genes, indicating that there is much more to be learned about autism genetics. While the current study is not large enough to confidently identify individual genes that have these rare inherited variants, we are learning more about these genes. Future research that focuses on multiplex families is increasingly important to yield novel insights.”

Pamela Feliciano, PhD, Scientific Director, Simons Powering Autism Research

Dr. Feliciano highlights that this research is the first step in a much greater investigation.

The scientists also added that their research affirmed their expectations that this class of rare inherited variants is more prominent in families with multiple members with autism than in families with only one affected individual. Substantial to the finding, children with ASD in such families are more likely to carry two of these variants when compared to their unaffected siblings.

The research also emphasized the need for greater diversity while conducting research of this kind, as researchers had fewer options to identify rare variants in people who belong to ancestral groups that are underrepresented in genomic research, including people of East Asian, African, and South Asian descent.

Journal reference:

Wilfert, A. B., et al. (2021) Recent ultra-rare inherited variants implicate new autism candidate risk genes. Nature Genetics.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of AZoLifeSciences.
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