DDX3X Gene Mutations Linked to Autism, Intellectual Disability
Sun, April 11, 2021

DDX3X Gene Mutations Linked to Autism, Intellectual Disability


More than a hundred mutations in DDX3, a protein-coding gene, has been linked to autism and intellectual disability. This is according to a new study published in the autism research news platform Spectrum.


Understanding DDX3X gene mutations

University of California, San Francisco professor of neurology Elliott Sherr and team explained that up to 3% of girls with unexplained intellectual disability are found to have a mutation in the DDX3 gene. More than 50% of these girls are also likely to have autism. DDX3 is “probably hugely important in regulating the on-and-off of important genes that are key for early development,” the co-lead investigator added.

The study likewise found different mutations in the DDX3 gene that lead to the severity and combinations of these traits. New York-based Seaver Autism Center for Research and Treatment’s assistant professor of psychiatry Silvia De Rubeis, who was not part of the recent study, commented that the findings are key to consider when looking at therapeutic approaches in the DDX3X syndrome.


The DDX3X syndrome

DDX3X is a disorder in females with intellectual disabilities or delays. The first women and girls reported with this recently discovered disorder were reported in 2014. The reason why it primarily affects girls is because of its location on the X-chromosome although there are also boys affected with the disorder. As of now, it has only been identified in about 300 individuals but doctors believe that it is the cause of 1 to 3% of all intellectual disabilities in females. It is also likewise misdiagnosed as autism spectrum disorder, Rett Syndrome, cerebral palsy, generic developmentally delayed label, or Dandy-Walker Syndrome (congenital brain malformation). The DDX3X syndrome has also been linked to low muscle tone, slower physical developments, abnormalities of the brain, seizures, and autism, shares nonprofit DDX3X Foundation, which was established to find a cure for the DDX3X syndrome.



Study method and kinds of gene mutations found

The genomes of 107 kids with mutations in their DDX3X gene were analyzed by Sherr and the team for their study. Almost all of the gene mutations arose spontaneously or “de novo” instead of being inherited. They also found that nearly one-third of these are nonsense mutations, which means that the gene fails to create the corresponding protein. Almost half are also missense mutations. In genetics, this kind of mutation happens when the change of a single base pair causes the substitution of different amino acid for another in the protein made by a gene, as defined by Genetics Home Reference in the US National Library of Medicine. Since nearly half are missense mutations, it led to the creation of a faulty protein.

Of the 57 kids found with missense mutations, they were found to have severe traits, such as the inability to walk, low muscle tone, and intellectual disability. Their brain scans also show that they have unusually small folds or ridges in the brain, a condition called polymicrogyria. The researchers found that three of the kids have the same gene mutation in the exact spot in their genomes and these three kids also have the same traits. This led the team to believe that the mutation is linked to the outcome.

While some may say it’s just a coincidence, Sherr said that the fact that the kids have the same phenotype and have the same mutations is already “compelling” to suggest the link between mutation and the specific outcome.



The group further suggested that the DDX3X gene is important for generating neurons during early brain development. Mice with a low level of DDX3X gene are found to have fewer neurons compared to their controls during their experiments. Duke University’s associate professor of molecular genetics and microbiology Debra Silver, who is the co-lead investigator, said that the main point of all their work is that the brain is “exquisitely sensitive” to the levels of DDX3X gene. A 25% reduction in the DDX3X level will already have a profound impact on the production of the neuron.

If there is low DDX3X level, it prevents the ribonucleic acid (RNA) from unwinding properly. Researchers also found that in mouse neural stem cells and neurons, missense mutations will cause the accumulation of proteins. Aside from the less than 500 people in the world diagnosed with  DDX3X syndrome, there may be more who are yet unidentified, Silver says. This is because the DDX3X gene’s link to intellectual disability was only discovered about five years ago. As their team has now identified more kids with the DDX3X mutations, their findings could help pinpoint the effects of certain gene mutations.

It is important to understand these links to make sure that people are getting the right treatments for certain gene mutations they carry. It is “critical” to get down to the functional part of the genes or the mutations happening within them and not just the genes in general, Washington University’s assistant professor of genetics’ Tychele Turner said. “This study is showing exactly why, in terms of DDX3X,” Turner added. DDX3X mutations mostly affect girls, so having a deeper understanding of how it works can also reduce the sex differences in conditions affecting brain development.



Prevalence of kids diagnosed with intellectual disability

From 2014 to 2016, the estimated prevalence of children aged 3 to 17 diagnosed with an intellectual disability was 1.48% for boys and 0.9% for girls.  The statistic is provided by database company Statista.

In 2017, scientific online publication Our World in Data shared the list of countries with the highest number of populations with idiopathic developmental intellectual disability, which is a category of disorders defined by impaired motor condition, visuospatial skills, and speech and language. These countries include India (4.46%), Yemen (3.51%), Sudan (3.46%), Afghanistan (4.09%), and Egypt (2.15%).

Globally, there are around 62 million people estimated to have had autistic spectrum disorder in 2016. Less than 50 million of these cases were males. While autism is more common in boys than in girls, the exact ratio is still unclear. Some experts believe that it could be because of the manner autism is diagnosed or defined. The estimated ratio is about 4.2 boys with autism for every girl.

In the future, scientists and doctors may use the genetic findings in the study of Sherr and the team to prevent, diagnose, treat, and cure illnesses and disorders.