Autism spectrum disorder (ASD) refers to a group of neurodevelopmental disorders that is characterized by abnormalities relating to social, behavioral, cognitive and language skills. The genetic architecture of ASD is comprised of a variety of rare mutations. These mutations includemonogenic conditions involving autistic symptoms. Furthermore, single nucleotide variants and de novo copy number variants add to disease susceptibility.
Inherited Factors Related to ASDs
Autosomal recessive loci are assisting scientists in understanding the inherited factors related to autism. Scientists are hopeful that the discovery of these mutations will offer them an opportunity to detect neurodevelopmental mechanisms in disease; thus, providing researchers with some amount of convergence that may be responsive to treatment intervention.
Genetic Research Sheds Light on Factors Contributing to the Development of an ASD
Research indicates that there could be almost 1000 genes contributing to an individual’s predisposition of developing an autism spectrum disorder. Although the genetic revolution enables scientists to identify a patient’s genetic etiology, the treatments available for ASD have remained the same. For instance, the US Food and Drug Administration has approved aripiprazole andrisperidone for the treatment of irritability in people who have an autism spectrum disorder; however, there are currently no drugs available to treat the two core characteristics of autism.
These two core characteristics include:
- Restrictive, repetitive patterns of activities, interests or behaviors
- Deficits in social interaction and communication
Individuals who have autism frequently receive therapy through behavioral treatments, includingapplied behavior analysis.
Recent Discoveries Related to Autism
Recent discoveries indicate that autism can occur due to polygenic or monogenic causes. Some genetic variants will be rare, with higher penetrance and larger effect sizes; whereas, others will be common variants with small effect sizes. A higher penetrance means there are fewer variables involved in bringing about the phenotype of interest, while a lower penetrance improves the likelihood that there are other genes and/or environmental issues playing a part in causing the ASD.
This diversity makes the development of treatments for these genetic disorders challenging. For this reason, the majority of efforts to develop treatment for neurodevelopmental disorders like autism has focused mainly on rare disorders that have a high penetrance of ASD.
The Effects of Valproic Acid in Utero
Contact with valproic acid in utero can lead to autistic symptomology; however, the co-occurrence of autism and Fetal Valproate syndrome are relatively small at approximately 10 percent. This suggests that there is a more complex issue to contend with when compared to AngelmanSyndrome. Approximately 80 percent of the individuals who have Angelman Syndrome show autistic symptomology.
Rare mutations accounting for a minority of ASD cases suggests that:
- An individual’s vulnerability could be the result of a variety of common variants (polygenic).
- Common variants in genes may play a small, although significant, role in an individual’s predisposition to autism; however, identifying these genes is extremely difficult. In order to attain the statistical power necessary for a relatively accurate result, large numbers of people need to be studied: Sometimes involving hundreds of thousands of people.
In addition, environmental agencies may play a role in determining an individual’s autistic phenotype, which varies from one individual to the next.
Whole Exome Sequencing (WES) Assisting Researchers in Identifying Mutations
According to a report published in the Journal of Autism and Developmental Disorders, with increasing frequency, researchers have been using whole exome sequencing (WES) as a means to identify mutations fundamentally associated with rare diseases, including intellectual disability and autism spectrum disorders. ID and ASD are genetically heterogeneous: Novel genes associated with these disorders are being identified quickly, which makes these disorders perfect candidates for WES.
One study involved a 17-year-old female with developmental delay, ASD, ID, Chiari I malformation, seizures, short stature and macrocephaly. WES found that she had de novo c.2028deIT (P677LfsX19) mutation in her SET domain-containing protein 2 (SETD2) gene. This finding offers evidence as to the potential role of SETD2 in intellectual disability and autism spectrum disorders. It also provides researchers additional details about the phenotypic manifestations of the mutations in SETD2.
Advances in neurobiology and genetics have allowed for the culmination in identifying molecular features that are common to a variety of genetically distinct forms of autism spectrum disorders. These discoveries have led to several potential treatment targets in some of the genetic disorders that are connected to autism. While the preclinical studies in mice are promising, none have been effective during clinical trials.
Even so, researchers have identified several hundred genes that may contribute to an individual’s susceptibility to an autism spectrum disorder. Researchers would like to see some of the therapies used for individuals who have tuberous sclerosis complex, fragile x syndrome and Rett syndrome as effective treatments for patients who have idiopathic ASD.
The Challenges of Developing Therapies forASDs
Limited knowledge concerning the underlying pathological mechanisms and the various factors that contribute to ASD makes developing disease-modifying therapies for individuals who have autism challenging.
Biomarkers May Allow for Personalized Therapeutic Strategies
Biomarkers that can be easily quantified may offer insight into an individual’s potential avenue for the creation of targeted, personalized therapeutic strategies. Ideally, biomarkers should provide researchers with quantitative measurements that may also be utilized as a means to evaluate treatment strategies to ensure they are efficient.
While intellectual disability (ID) affects less than 1 percent of the population, up to 80 percent of these individuals’ underlying etiology has yet to be discovered; however, researchers believe that chromosomal abnormalities account for the majority of these aberrations.