Unraveling the genetic causes of Autistic Spectrum Disorder

Andréa Laurato Sertié, PhD

Symptoms and epidemiology of Autistic Spectrum Disorder

Autistic Spectrum Disorder (ASD) encompasses a group of neurodevelopmental disorders that are characterized by impaired ability to socially interact and communicate, and by the presence of stereotyped and repetitive behaviors. These symptoms can vary widely among patients (they may be mild, moderate or severe) and other clinical manifestations may be present, such as intellectual disability, epilepsy, anxiety, macrocephaly and hypotonia, among others [1].

Recent epidemiological studies conducted in the United States show that ASD has a prevalence of approximately 1 in 59 individuals among the population, being four times more common in boys than in girls [2]. The World Health Organization (WHO), subordinated to the UN, considers that on average 1 in 160 children is within the autism spectrum.

It is important to comment that the prevalence of ASD has increased substantially worldwide over the years, which, among other reasons not yet defined, involves greater efficiency in early diagnosis and changes in the practices for identifying the disorder.

Genetic aspects of Autistic Spectrum Disorder

Although environmental factors, such as infections and exposure to certain toxic agents during pregnancy, can increase the risk of developing ASD, it is known that genetic factors have a very important contribution to the etiology of this disorder. Based mainly on studies of familial recurrence and concordance between monozygotic and dizygotic twins, estimates of TEA heritability have varied between 38 and 90% [3]. Thus, there is no doubt that DNA can contain changes in its sequence of bases, called genetic variants here, that cause or contribute to ASD! But, what do we know today about the genetic causes of ASD?

Especially through the use of more recent genomic analysis methodologies on a large scale, such as CGH arrays (comparative genomic hybridization) and the sequencing of a new generation of exomes or genomes, it is possible to identify rare and high-risk genetic variants (that is, responsible for the clinical picture) in approximately 25% of the patients. About 15% of cases have copy number variations – CNVs – of genomic segments, which can occur on any chromosome, although there are some regions with more frequent CNVs, such as those located in 15q11-q13 , 16p11.2 and 22q13 which combined are present in about 3-5% of cases. The last 10% of cases have non-synonymous and deleterious point variants in several candidate genes for ASD. Yet, in many patients, not only one rare genetic alteration is identified, but two or more in a model called inheritance oligogen (oligogenic = of a few/few genes).

These genetic variants may come from one or both parents, even though they do not have ASD or have only very slight signs of the disorder. These variants can also arise in the formation of the egg or sperm and, therefore, are only found in children with ASD, which we call new genetic variants. Currently, more than two hundred CNVs and at least 800 candidate genes for ASD have been identified, 140 of which are already known to cause ASD when they have harmful variants (Simons Foundation Austism Research Initiave). It is important to note that none of these genes individually can explain more than 1% of the total cases of ASD, and the genetic cause is still unknown in approximately 75% of cases.

A significant portion of ASD cases of unknown cause appear to follow a multifactorial model of inheritance, in which the disorder is the result of a combination of more frequent and low risk genetic factors associated with predisposing environmental factors. In these situations, little is known about which and how many genetic variants per individual are needed to cause ASD. Thus, ASD can be considered a complex disease, and may involve different mutational mechanisms and inheritance models. Because of this complexity, knowledge about the genetic causes of ASD has required a lot of effort, high costs and has evolved more slowly.

Challenges in the study of the genetics of Autistic Spectrum Disorder

One of the limitations of large-scale genomic analysis methodologies is the interpretation of the findings, since most of the time changes of unknown significance are identified and the tests, therefore, are not conclusive. Thus, the largest current challenges are to determine which variants among the several genetic variants identified by genomic analyzes are in fact involved in the etiology of the disease, how many variants are necessary for the complete penetration of ASD, and how these variants converge in common biological pathways that result in the disease in each patient.

One strategy to try to unravel the possible clinical significance of candidate variants is to conduct functional studies to verify which of the variants are sufficient to cause morphological and functional changes in neural cells, which must be associated with the pathophysiology of the disease. But how to analyze neural cells derived from patients with candidate genetic variants in view of the impossibility of performing brain biopsies and the difficulty of obtaining post-mortem samples of brain tissues?

Our research group at Hospital Israelita Albert Einstein has used it as an experimental model to understand the molecular mechanisms of TEA induced pluripotent stem cells (iPSC), which are obtained through reprogramming of somatic cells and are similar to embryonic stem cells, and can be differentiated into cell types from any of the three embryonic leaflets, including neural progenitor cells, neurons and glial cells. The great advantage of this technique in the study of TEA is that the strains obtained have the genome of the donor patient and, therefore, constitute a model of cells in vitro already predisposed to the disease.

Thus, in our research projects we carry out different functional analysis with neuronal cells and glial cells derived from iPSC of patients with ASD (such as analysis of gene and protein expression, analysis of the activity of intracellular signaling pathways, analysis of proliferation, differentiation and migration), and we try to integrate the findings with the cells and the data obtained with genomic analysis. For example, using iPSC-derived neural progenitor cells from a patient with ASD carrying rare variants in the RELN gene, which encodes Relina that controls neuronal migration and synapse function, our group recently showed that variants are deleterious and lead to decreased secretion of Relina and the activity of its signaling path [5]. Still, unpublished data from our group show that the same patient has a rare variant in another gene, CACNA1H, which encodes the α¹ subunit of a type T calcium channel, and that this variant is also deleterious and contributes to the Relina dysfunction. This work is the first to show that deleterious variants in different genes are correlated to the increase of risk of ASD in an oligogenic model of inheritance.

We believe that knowledge of the genetic causes of ASD can bring important contributions to the early diagnosis of this disorder, to the genetic counseling of families and to the development of more targeted and efficient therapeutic strategies for each patient.

About the Author: 

Andréa Laurato Sertié is graduated and PhD in Biological Sciences from the University of São Paulo. She is currently a researcher at the Instituto Israelita de Ensino e Pesquisa Albert Einstein. Has experience in Molecular Biology and Human and Medical Genetics.


[1] An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature. 1998 Feb 5;391(6667):594-7

[2] Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):865-7.

[3] Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868-71.

[4] Zanluca, Camila et al. “First report of autochthonous transmission of Zika virus in Brazil.” Memórias do Instituto Oswaldo Cruz vol. 110,4 (2015): 569-72. doi:10.1590/0074-02760150192.

[5] Pesquisa de Vírus de RNA e Genotipagem – PLASMA (EDTA- GEL). Disponível em: <!6811>.

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