ASD is an Autism Spectrum Disorder that represents a group of congenital mental, neurological and developmental conditions. It has a proven genetic foundation. Various genes and pathways are involved in causing varied degrees of ASD.
Learn about the genetics, mechanisms and genes involved in Autism Spectrum Disorders in this article.
Stay tuned.
Related article: 5 Common Genes Linked to Congenital Neural Tube Defects.
Disclaimer: The content presented herein has been compiled from reputable, peer-reviewed sources and is presented in an easy-to-understand manner for better comprehension. A comprehensive list of sources is provided after the article for reference.
Key Topics:
What is ASD?
ASD is an Autism Spectrum Disorder– a polygenetic and congenital genetic abnormality. It is categorized as a collective neurodevelopmental problem. It represents challenges in mental and developmental conditions including social interactions, repetitive behavior, communication and several degrees of mental retardation.
Thus, it affects an individual’s daily life and quality of life as well. It usually occurs during childhood and remains lifelong. However, the severity of symptoms usually depends on the severity of ASD and so varies from patient to patient.
While the exact etiology of ASD remains unclear and multifaceted, a significant component, genetic factors and their interaction with the environment is one key component that causes ASD.
It’s a congenital condition that occurs during early embryonic development due to unknown reasons. But results, mostly in mental retardation and learning and cognitive malfunctions.
The genetic foundation and various genes involved in ASD are discussed here.
Genetic Basis of Autism Spectrum Disorders:
Genetic factors play a substantial role in the development of ASD. Numerous genes associated with brain development, synaptic function, and connectivity are associated with ASD.
Studies suggest that over 1000 genes can be associated with various types of ASD, however, among which ~100 genes are now known, studied well and have a strong link with ASD.
Common conditions involved in ASD are gene mutations, epigenetic alterations, copy number variations, numerical and structural chromosomal abnormalities, SNPs, etc.
Inheritance:
Autism Spectrum Disorders are complex genetic abnormalities with unclear inheritance patterns. Lauren and Alicia (2019) demonstrate that 40 to 80% of ASD cases are inherited. However, both genetic and environmental factors collectively impact the overall penetration of the condition.
For example, Fragile X syndrome and Tuberous Sclerosis have a clear inheritance pattern while idiopathic ASD and 22q11.2 Deletion syndrome don’t have a clear inheritance pattern.
Related article: Different Types of Genetic Inheritance Patterns.
List of Inherited ASD:
| ASD | Inheritance pattern | Genes involved |
| Fragile X syndrome | X-linked dominant | FMR1 |
| Rett Syndrome | X-linked dominant | MECP2 |
| Tuberous Sclerosis | Autosomal dominant | TSC1 and TSC2 |
| Angelman syndrome | Unclear | UBE3A |
In addition to the gene mutations, certain chromosomal abnormalities can contribute to the risk of ASD. For example — Fragile X syndrome, caused by a mutation in the FMR1 gene on the X chromosome, is associated with a higher prevalence of ASD. Chromosomal deletions and duplications can also contribute to the risk of ASDs.
In conclusion, the genetics of ASD are highly heterogeneous and don’t have a clear inheritance pattern (collectively). It occurs usually due to the interplay between genetic and environmental factors.
>>Read more: What is Deletion Syndrome? Top 6 Chromosomal Deletion Syndromes Explained.
List of all genes involved in ASD:
SHANK3, NLGN3, NLGN4X, MECP2, FMR1, UBE3A, TSC1, TSC2, PTEN, CACNA1C, CNTNAP2, FOXP1, FOXP2, DYRK1A, CDKL5, ADNP, ARID1B, CHD8, SCN2A, SCN1A, GRIN2B, NRXN1, CNTN4, GABRB3, MET, EN2, WDFY3, KMT2E, ANK2, NR3C2, UBE3B, NR4A2, STXBP1, MTHFR, SH3RF3, ATRX, RIMS1, AUTS2, NRXN3, PTPRG, SYNGAP1, KCNQ2, CHD2, GRIN2A, SMARCA4, CTNNB1, SETD5, SATB2, SLC6A1, and SLC25A12.
Common Genes:
- SHANK3 (SH3 and multiple ankyrin repeat domains 3)
- CHD8 (Chromodomain helicase DNA-binding protein 8)
- SCN2A (Sodium voltage-gated channel alpha subunit 2)
- NRXN1 (Neurexin 1)
- CNTNAP2 (Contactin-associated protein-like 2)
- FMR1 (Fragile X mental retardation 1)
- ADNP (Activity-dependent neuroprotector homeobox)
- TSC1 (Tuberous sclerosis Complex 1)
- TSC2 (Tuberous sclerosis Complex 2)
- PTEN (Phosphatase and tensin homolog)
Rare genes:
- CNTNAP2 (Contactin-associated protein-like 2)
- FMR1 (Fragile X mental retardation 1)
- ADNP (Activity-dependent neuroprotector homeobox)
Genetic Mechanism:
As aforementioned, genetic factors, epigenetic alterations, neurological conditions, and chromosomal abnormalities are likely to increase the risk of ASD. Let’s explain each mechanism one after another.
Gene-gene interactions:
Numerous genes have been linked to ASD, highlighting its strong genetic correlation. Mutations in genes associated with synaptic function, neuronal development, and connectivity play a pivotal role.
For example, genes like SHANK3, involved in synapse formation, and MECP2, involved in regulating gene expression, are associated with ASD. The interplay of these genes affects the excitatory and inhibitory signals in the brain, influencing cognitive and social development.
CNTNAP2 and NLGN3, are crucial for the formation and maintenance of synapses. Mutations in either or both genes can impact communication between nerve cells, contributing to social and cognitive problems in individuals with ASD.
FOXP1, TSC1, and TSC2 are crucial for the development, migration and differentiation of neurons. Mutation in these genes disrupts neuronal development and is likely to increase the risk of ASD.
Chromosomal abnormalities:
Structural and numerical chromosomal abnormalities result in varied degrees of ASDs. If a chromosomal part is deleted or inserted, it causes ASDs. For example, 22q11.2 Deletion Syndrome. Here, a small part of the q arm on chromosome 22 deletes and increases the ASD risks.
Fragile X and Rett syndromes are two more examples of chromosomal alterations in ASDs. We already have discussed this. In short, as ASD is a polygenic and complex genetic condition, it is difficult to discuss all the mechanisms behind ASDs.
Epigenetic mechanisms:
In addition to these two common genetic factors, alterations in gene expression (epigenetic changes) also contribute to ASDs. Studies manifest that DNA methylation, non-coding RNAs, histone modifications, chromatin remodeling and genetic imprinting are associated with various types of ASD.
One recent study depicts that 19.5% of ASD genes increase the risk of ASD phenotypes through various epigenetic mechanisms. However, much like the genetic foundation, the underlying epigenetic mechanism behind ASD is much complex too.
Read more: Epigenetics 101: What is Epigenetics and How Does It Work?
Environmental Factors:
Prenatal exposures to factors like certain medications, toxins, infections, or maternal stress are environmental factors that may influence neurodevelopment and cause ASDs. Additionally, advanced parental age at conception has been linked to an increased risk of ASD.
Notedly, gene-environment interplay is less studied but most common in the present condition.
Read more: Influence of Gene-Environment Interaction on life.
5 Important Genes Linked to ASD:
SHANK3 (SH3 and Multiple Ankyrin Repeat Domains 3)
- Location: Chromosome 22
- Function: SHANK3 is essential for the formation and function of synapses.
- Role in ASDs: SHANK3 plays a crucial role in synaptic development and function, and disruptions in its function can contribute to the neurological and behavioral characteristics observed in ASDs. Mutations in SHANK3 have been identified in individuals with ASDs.
NRXN1 (Neurexin 1)
- Location: Chromosome 2
- Function: synaptic adhesion and providing communication between neurons are the key functions of NRXN1.
- Role in ASDs: NRXN1 is crucial for proper synaptic connectivity, and alterations in its function can disrupt neural communication, contributing to the complexity of ASD phenotypes. Mutations in NRXN1 have been associated with an increased risk of ASDs.
CNTNAP2 (Contactin-Associated Protein-Like 2)
- Location: Chromosome 7
- Function: Neural development and regulation of synaptic functions are two key functions of the CNTNAP2 gene.
- Role in ASDs: CNTNAP2 plays a role in the formation of neural networks, particularly in brain regions associated with language development and social cognition. Mutations in CNTNAP2 have been linked to language-related traits and an increased risk of ASDs.
PTEN (Phosphatase and Tensin Homolog)
- Location: Chromosome 10
- Function: PTEN is a tumor suppressor gene that regulates cell growth and division.
- Role in ASDs: PTEN is crucial for neuron division, growth and connectivity, and alterations in its function can contribute to abnormal brain development and related traits. PTEN mutations have been identified in individuals with ASDs.
FMR1 (Fragile X Mental Retardation 1)
- Location: X-chromosome
- Function: FMR1 is involved in synaptic plasticity and mRNA metabolism.
- Role in ASDs: FMR1 is vital for synaptic plasticity, and disruptions in its function can contribute to cognitive and behavioral challenges observed in ASDs. Expansion of the FMR1 gene leads to Fragile X syndrome, a genetic condition often associated with ASD features.
Recent Research:
Wang et al (2023) studied 13,052 ASD patients and identified a new gene MAGEC3, located on the X chromosome clustering ASD-causing variants. Harmful mutations inherited from the mother, from this region including the MAGEC3 gene, are linked to a higher risk of ASD in males.
Wrapping up:
In conclusion, despite having a complex genetic foundation, these five crucial genes—SHANK3, NRXN1, CNTNAP2, PTEN, and FMR1 play a key role and increase the likelihood of Autism Spectrum Disorders in patients.
Understanding the genetic mechanism of autism spectrum disorders helps in diagnosis prevention, management and therapy development. Genetic tests such as Genome-wide studies or whole genome sequencing help in measuring the polygenic risk for ASD.
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Resources:
- Rylaarsdam L, Guemez-Gamboa A. Genetic Causes and Modifiers of Autism Spectrum Disorder. Front Cell Neurosci. 2019 Aug 20;13:385. doi: 10.3389/fncel.2019.00385.
- Wang, S., Wang, B., Drury, V. et al. Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD. Nat Commun 14, 8077 (2023). https://doi.org/10.1038/s41467-023-43776-0.
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