Clinical Neurology and Neuroscience

2024, Vol. 8, No. 4, pp. 47-53

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Research Article :
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Effect of Genetics on Autism Spectrum Disorders: A Review /
Study w
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Raneem Nabil Halaweh* .
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Royal College of Surgeons in Ireland, Medical University of Bahrain, Bahrain, Ireland c
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Abstract e
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Autism Spectrum Disorders (ASD) are intricate neurodevelopmental conditions marked by challenges in social interaction,
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communication, and repetitive behaviors. The etiology of ASD is multifaceted, involving genetic mutations, perinatal,
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nutritional and environmental factors. This review explores the various genetic mutations implicated in the development of
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ASD for the purpose of examining the diverse genetic factors contributing to the pathogenesis of ASD such as SHANK3,
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SCGN, ADNP, ARID1B, CHD8, DYRK1A, KMT2C, OT, AVP and zinc transporter genes. A comprehensive review of
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literature was conducted to gather information on genetic influences related to ASD. Studies investigating the complex
interplay of those factors were analyzed to elucidate how they contribute to the development of ASD. Results found that
genetic mutations in genes like Shank3 and SCGN have been identified as playing a role in the pathogenesis of ASD through
their impact on glutamic excitatory pathways and oxytocin signaling. ADNP, ARID1B, CHD8, DYRK1A, KMT2C, OT, AVP
and zinc transporter genes have also been linked to an increased risk of ASD and associated cognitive and neurological
impairments. In conclusion, research on different genetic mutations and deletions affecting autism spectrum disorder (ASD)
highlights the complexity of the disease. Key genes such as SHANK3, SCGN, ADNP, ARID1B, CHD8, DYRK1A, and
KMT2C are implicated, each contributing uniquely to ASD. Genetic variations, mutations, and heritability play significant
roles, with factors like zinc deficiency and advanced paternal age also linked to increased ASD risk. While genomic technology
has identified specific markers and pathways, the effect of multiple genetic mutations on symptom severity remains unclear.
Understanding these genetic factors is crucial for improving diagnostic precision and developing targeted therapies,
necessitating continued interdisciplinary research.

Keywords
ASD, SHANK3, SGGN, ADNP, ARID1B, CHD8, DYRK1A, KMT2C

1. Introduction
Autism Spectrum Disorders (ASD) are a group of neuro- nosed at any age, but symptoms usually start manifesting
developmental conditions defined by the Diagnostic and Sta- during early childhood. Therefore, early diagnosis of ASD
tistical Manual of Mental Disorders, Fifth Edition (DSM-5) might be associated with better prognosis for an individual.
as challenges in social communication and interaction, re- While no cure for ASD is found to date, family education is
stricted interests and repetitive behaviors. ASD can be diag- important for a better quality of life and adaptation with the

*
Corresponding author:

Received: 18 October 2024; Accepted: 4 November 2024; Published: 26 November 2024

Copyright: © The Author (s), 2024. Published by Science Publishing Group. This is an Open Access article, distributed
under the terms of the Creative Commons Attribution 4.0 License ([Link] which
permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
Clinical Neurology and Neuroscience [Link]

disease. Treatment modalities for the child such as behavior- also demonstrated that SHANK3 mutant macaques demon-
al therapies, speech and language therapy and occupational strated reduced overall activity on actigraphy compared to
therapies are also important. [1] The purpose of this paper is controls. They also demonstrate longer sleep latency and
to review and synthesize current knowledge regarding the increased awakening both indicating reduced efficiency of
genetic factors associated with ASD. By exploring these ge- sleep a symptom in ASD patients. [6]
netic underpinnings, this research aims to enhance our un- Malara et al. found that mutations in the SHANK3 gene
derstanding of the biological mechanisms driving ASD and leads to myelination in the central and peripheral nervous
to identify potential avenues for targeted interventions. The system contributing to Phelan-McDermid Syndrome
significance of this research lies in its potential to bridge (PMDS), a subset of ASD. Patients with PMDS have muta-
gaps in our understanding of ASD's complex genetic land- tions in chromosome 22 and exhibits autistic like behavior in
scape. Insights gained from this study could pave the way for addition to chewing of non-food items, decreased perception
more accurate diagnostic tools and personalized therapeutic of pain and regression of skills. They found SHANK3 gene
approaches, ultimately improving outcomes for individuals expression in oligodendrocytes and schwann cells responsi-
with ASD. As the field continues to evolve, interdisciplinary ble for myelination in the nervous system. Magnetic reso-
research efforts will be crucial in unraveling the intricate nance imaging revealed that SHANK3 mutant mice showed
relationship between genetic predisposition and neurodevel- reduced volume in the corpus callosum as seen in PMDS
opment, fostering better support for individuals on the autism patients. They also observed alteration in the number and
spectrum. maturation of myelin related cells in the nervous system in
SHANK3 mutant mice. All these changes contributed to the
symptoms found in PMDS patients. [7]
2. Genetic Factors Vyas et al. found an interesting relationship between the
SHANK3 mutation and zinc. They found that SHANK3 mu-
Autism Spectrum Disorder (ASD) is a complex neurode-
tations caused a decrease in synaptic density and excitatory
velopmental condition influenced by a myriad of genetic
neurotransmission as mentioned earlier. However, the inter-
factors. Research has identified numerous genes implicated
esting part of the research is the prevention of structural and
in ASD, contributing to its heterogeneous nature. From syn-
functional deficits in SHANK3 deleted genes with in vitro
aptic communication regulators to genes involved in neu-
zinc supplementation. Thus, zinc supplementation has been
ronal development, these genetic variations offer crucial in-
indicated as a potential therapy in those patients. This in turn
sights into the underlying mechanisms of ASD. [2]
also explains why mutation in some zinc transporter genes
mentioned below have been implicated in ASD. [8]
2.1. SHANK3 Gene Deletion/Mutation
SHANK3 is a scaffolding protein that helps bind gluta- 2.2. Secretagogin Gene (SCGN) Deletion
mate excitatory neurotransmittor to postsynaptic terminal in
Liu and colleagues conduced a cohort study using whole
the brain. Therefore, deletion of the protein will lead to the
exome sequencing of ASD bands on 168 children and their
loss of excitatory synapse and the underactivation of those
parents. Individuals were recruited based on diagnosis of
receptors. This deletion is thought to contribute to some of
ASD by Childhood Autism Rating Scale (CARS) and Autism
the characteristics of ASD patients. [3]
Behavior Checklist (ABC). Among 168 participants two
Peça et al. studied Shank3 homozygous mutant mice
male patients were identified to carry heterozygous mutation
which displayed autistic like behavior. SHANK3 deletion
in the SCGN gene both inherited from their mothers. This
demonstrated social interaction deficits which is the main
mutation altered the 5’ intron splicing at the site following
recognizable symptom in people with ASD. [4]
exon 10 resulting in protein degradation and loss of function.
Guo et al. also found evidence that SHANK3 gene muta-
These participants presented with autistic like behavior such
tion in the anterior cingulate cortex (ACC) lead to the loss of
as defects in communication, social interaction, and devel-
dendritic spines and impairment of the synaptic excitatory
opmental delay. [9] They also examined oxytocin levels in
pathway in the ACC region of the brain resulting in the un-
brains of children with ASD and healthy volunteers and
deractivity of the area which results in the social interaction
found that in healthy control oxytocin levels ranged from
deficits seen in patients with ASD. [5]
24-47 pg/ml compared to ASD diagnosed patients with levels
Zhou et al. studied the relation of SHANK3 genes to ASD
approximating 13-19 pg/ml. [10]
symptoms in monkeys. They used the CRISPR-Cas9 tech-
Another article by Liu et al. found that Secretagogin gene
nology to produce mutations in SHANK3 genes in macaques
(SCGN) deficiency is another risk factor for ASD. SCGN is
monkeys and their first generation offspring. Their results
a gene that regulates synaptic transmission of oxytocin. De-
showed that mutations in the genes altered brain circuit con-
letion of SCGN in zebrafish and mice models showed dis-
nectivity exhibiting sleeping disturbances, motor deficits,
ruption of oxytocin signaling at the synaptic cleft causing
social and learning impairments as well as repetitive behav-
inflammation. The consequence of this is the development of
iors all typical symptoms of ASD. In addition, Zhou et al.

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autistic like behavior and an impairment of brain develop- density and gene expression patterns as well as characteris-
ment. [11] tics of ADNP syndrome such as developmental, motor and
Liu et al. then used the CRISPR/Cas9 editing tool to gen- cognitive delays. [15]
erate animal models with SCGN deletion to study the effect
on Zebrafish behavior. In a swimming test, homozygous 2.4. ARID1B Gene Mutation
SCGN rich zebrafish (SCGN+/+) were found to prefer
swimming shorter distances compared to both homozygous AT-Rich Interaction Domain 1B (ARID1B) gene has been
and heterozygous SCGN deficient zebrafish (SCGN -/- and shown to modulate bone growth via the regulation of
SCGN +/-). In another test, two Zebrafish were placed on Wnt/B-catenin pathway leading to growth and development.
one side of a plastic board and a single animal of SCGN+/+, Mutations in such gene has been associated with intellectual
SCGN -/- and SCGN +/- was placed on the other side of the disability and ASD. [16] Moffat et al. used ARID1B gene
board. SCGN+/+ exhibited higher tendency to move towards knockout mice to determine its association with ASD. Their
the group of two zebrafish than either SCGN -/- and SCGN results showed that mutation in the gene resulted in de-
+/- thus establishing the effect of gene deletion on social creased cell proliferation in the cortical and ventral neural
interaction and grouping preference seen in ASD patients. cells as well as alteration in cell cycle regulation and in-
The amount of time interacting with others spent by each creased cell death. Therefore, gene mutation has been shown
zebrafish in a visually mediated social preference test con- to affect neurogenesis and the inhibitory progenitor cells
ducted by the researchers was found at 63.1%, 8.2% and 6.1% with effects leading to typical manifestations of ASD.
of the time for each of SCGN+/+, SCGN +/- and SCGN -/- Therefore, Understanding the role of ARID1B in neural
respectively. [12] function and growth regulation sheds light on the pathogene-
Finally, researchers continued their study to see the effect sis of ASD and provides insights for potential therapeutic
on brain development of those knockout animals. Their re- interventions. [17]
sults showed that 25% of the SCGN +/- and 37% of SCGN Smith et al. produced mutations were one allele of the
-/- were microcephalic compared to 2% of SCGN +/+ ARID1B gene was deleted either in the parvalbumin or so-
zebrafish. They also used cell proliferation marker pHH3 and matostatin interneurons to examine symptoms of ASD and
found that homozygous SCGN depleted Zebrafish displayed intellectual disability. ARID1B deletion in the parvalbumin
a one-third reduction of pHH3 levels and hence reduced cell interneuron (PV) resulted in ASD symptoms of social and
proliferation compared to SCGN +/+ models. PCR technique emotional impairments, while deletion in the somatostatin
was also conducted on the hypothalamus of SCGN +/+ and interneurons (SST) caused stereotypical behaviors, learning
SCGN -/- zebrafish animals. This test established that SCGN and memory deficits. These findings indicate importance of
deficiency results in up-regulation of pro-inflammatory cy- the ARID1B gene in the PV and SST interneurons and its
tokines IL-6 and TNF as well as a disruption in oxytocin relation to phenotypic characteristics of ASD patients. [18]
pathway related genes such as Oxt, Ppp3cb and Plcb3 pro-
duced by the hypothalamus. Oxytocin related genes were 2.5. CHD8 Gene Mutation
found decreased by 31% in SCGN deficient zebrafish. [11]
Chromodomain helicase DNA-binding 8 (CHD8) gene has
2.3. ADNP Gene Mutation been associated with risk of ASD. The gene mutation has
been found to disrupt inhibitory and excitatory neurons
The activity dependent neuroprotector homeobox (ADNP) leading to developmental alterations which mimic ASD
gene, essential for brain formation, has been associated with symptoms. [19] Shi et al. generated two embryonic stem
increased risk of ASD. Within 116 participants, Arnett et al. cells with CHD8 loss of function mutation and examined the
found that mutations in the ADNP gene led to disruptions in effect. Electrophysiological studies revealed a 3-fold de-
intellectual disability compared to controls. In addition, mu- crease in neuronal firing and synaptic activity because of this
tations in the gene has been associated with social impair- mutation. There was also a large effect on chromatin struc-
ment as well as restricted and repetitive behaviors seen in ture especially near a transcription regulator implicated in
ASD patients. [13] ASD known as autism susceptibility candidate 2 (AUTS2).
More specifically, the ADNP gene mutation has been These mutations resulted in intellectual disability and symp-
shown to particularly mimic the autism-like ADNP syndrome. toms of ASD compared to healthy control. [20]
This syndrome is characterized by developmental delay, in- Kerschbamer et al. results showed that suppression of
tellectual disability, speech impairments, motor dysfunction CHD8 gene altered histone maintenance and RNA pro-
and autism. It is caused by mutations in ADNP gene which is cessing, important regulatory processes in ASD. They stud-
involved in chromatin regulation and DNA methylation. [14] ied the effect of CHD8 suppression on histone modification
Sragovich et al. developed ADNP mutant mice which exhib- by analyzing pluripotent neural progenitor stem cells. CHD8
ited the same symptoms as autism-like ADNP syndrome in suppression led to 47.82% reduction in histone expression
humans. Their mice displayed the same defect in synaptic impacting transcription factors and alteration in splicing

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mechanism of genes involved in RNA processing. This alter- 2.9. Zinc Transporter Genes Mutation/Deletion
ation in transcription mechanisms and histone expression are
factors that contribute to increased risk of ASD. [21] In another study a group of 0-3 years old male and female
While another study by Li et al. used the CRISPR-Cas9 patients with autism there was a total zinc reduction of 43.5%
technology to show how CHD8 gene mutations cause an and 52.5%, respectively. This deficiency contributes to neu-
enlargement in brain size also known as macrocephaly in ropsychological symptoms of autism and learning impair-
non-human primates. Mutations in CHD8 gene in monkeys ment by affecting glutamate excitatory effect on the synapse.
led to increased number of glial cells and gliogenesis result- Toxic levels of glutamate are also associated with seizures,
ing in macrocephaly, a phenotypic feature of some ASD pa- thus why some patients with Autism suffer from epilepsy.
tients and contributed to other symptoms of the disease. [22] [29]
Ellingford et al. studied the effect of CHD8 gene on Yoo et al. suggested that zinc transporter 3 (ZnT3) deletion
ASD-associated cortical circuits by studying synaptic trans- during early brain development may contribute to ASD.
mission in prefrontal cortex in CHD8 mutated mouse model. Their results found that at 4-5 weeks of age, male mice with
They report alteration in excitatory and inhibitory synaptic ZnT3 deletion demonstrated autistic like behavior as well as
transmission associated with disruption of homeostatic plas- increased cortical volume and neuronal density. [30]
ticity mechanisms and ASD-relevant circuits in the cortex.
[23] 2.10. Neuroglinin-3 (NLGN3) Gene
An interesting journal published by Camasio et al. linked
2.6. DYRK1A Gene Mutation
neuroanatomical abnormalities with genes associated with
Dual-specificity tyrosine phosphorylation-regulated kinase autism. Researchers found that decreased grey matter volume
1 (DYRK1) is a gene that was found to be disrupted in ASD was associated with autistic related genes in areas responsi-
patients which exhibits phenotypic features of the disease. ble for dorsal attention and cerebellar network. In addition,
Mutations in one allele of the DYRK1A gene resulted in increased grey matter volume was associated with genes
intellectual disabilities and speech difficulties. Earl et al. located in the somatomotor, limbic and thalamic systems.
found that 89% of patients with DYRK1A mutations pre- The most significantly correlated gene found was Neurolig-
sented with at least five autistic like symptoms. [24] in-3 (NLGN3), associated with both decrease and increase in
Raveau et al. developed frameshift mutations in the gene grey matter volume. The NLGN3 is a cell adhesion protein
in mouse models resulting in elimination of its kinase activi- important in neuronal synaptic signalling pathway. This gene
ty. Those mice models demonstrated impairments in cogni- has been previously found to be associated with autism. [31]
tion, communication and social interaction like in ASD pa- A study by Gutierrez et al. found that ASD caused mutations
tients. [25] in the Neuroligin-3 (NLGN3) gene which causes decreased
synchronicity and signalling between different brain regions
which in turn causes decreased neuronal connectivity. [32]
2.7. KMT2C Gene Mutation
Other genes associated include the SHANK3 gene involved
Lysine N-methyltransferase 2C (KMT2C) is an enzyme in neural signalling spoken of earlier. [31]
involved in histone modification. Brauer et al. used
CRISPR/Cas9 gene editing tool to study the effect of
KMT2C gene knockout in mouse model. Those knockout 3. Genetic Imprinting and
animals exhibited ASD related symptoms such as repititive Hypomethylation
behavior, social deficits and intellectual disability. [26]
Advanced paternal age
Reichenberg et al. found an association between advanced
2.8. Oxytocin and Vasopressin Receptors
paternal age and risk of Autism in offspring. Their results
Studies have found an association between oxytocin (OT) suggest that men over the age of 40 are 5.75 times more
and vasopressin (AVP) receptors genes and ASD phenotype. likely to have children born with ASD than men under the
Single nucleotide polymorphisms in AVPR1 and OXTR re- age of 30 years. The cause of this finding is likely due to de
ceptors were genotyped in families with ASD. Mutations in novo mutations and genetic imprinting that occur with ad-
those receptors was associated with social withdrawal and vanced paternal age. Genetic imprinting is the expression of
repititive behaviors related to ASD. [27] either maternal or paternal allele. When the imprinted gene
In addition, genetic polymorphism in the AVPR1A pro- expressed is of paternal origin, the maternal gene is silenced,
motor region has been identified to be associated with social i.e. not expressed and vice versa. [33]
deficits in autistic children. [28] Atsem et al. studied the role of demethylation in certain
genes found in Autism. In their study methylation process of
two alleles FOXK1 and KCNA7 in sperm samples of 25-35
years old and 40-55 years old. FOXK1 is a transcription reg-

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ulator and KCNA7 is a gene that codes for potassium chan- DSM-5 Diagnostic and Statistical Manual of Mental
nel. Their results showed that sperm of older men displayed Disorders, Fifth Edition
reduced methylation and a tendency towards hypomethyla- SHANK3 SH3 and Multiple ankyrin repeat domains 3
tion compared to younger sperm. [34] ACC Anterior Cingulate Cortex
The journal of neuroscience published a paper by Foldi et al. PMDS Phelan-McDermid Syndrome
that also studied the effect of advanced paternal age on Au- CARS Childhood Autism Rating Scale
tism. They compared mice of 12-18 month old with 4 month ABC Autism Behavior Checklist
old controls through behavioral testing and neuroanatomy. SCGN Secretagogin Gene
Overall, their older mice showed a phenotype characteristic of ADNP Activity Dependent Neuroprotector Homeobox
Autism such as increased anxiety and exploration tendency ARID1B AT-Rich Interaction Domain 1B
and decreased learning compared to controls. Their older PV Parvalbumin Interneuron
mice also showed a thinner cortex at birth and increased cor- SST Somatostatin Interneurons
tical volume as adults, both characteristics of autistic brain. CHD8 Chromodomain Helicase DNA-binding 8
[35] AUTS2 Autism Susceptibility Candidate 2
RNA Ribonucleic Acid
CRISPR Clustered Regularly Interspaced Short
4. Conclusion Palindromic Repeats
Cas9 CRISPR-associated Protein 9
In conclusion, the study of genetic factors associated with
DYRK1A Dual-Specificity Tyrosine
autism spectrum disorder (ASD) underscores the complexity
Phosphorylation-Regulated Kinase 1
and diversity of its etiology. While significant progress has
KMT2C Lysine N-Methyltransferase 2C
been made in understanding various aspects of ASD, much
OT Oxytocin
remains to be elucidated. Research has highlighted the sig-
AVP Vasopressin
nificant role of genetic variations, mutations, and heritability
ZnT3 Zinc Transporter 3
in predisposing individuals to ASD. The studies reviewed
FOXK1 Forkhead Box K1
highlight various genes such as SHANK3, SCGN, ADNP,
KCNA7 Potassium Voltage-Gated Channel Subfamily A
ARID1B, CHD8, DYRK1A, KMT2C, and others, each con-
Member 7
tributing uniquely to the complex genetic landscape of ASD.
NLGN3 Neuroligin-3
Furthermore, studies on zinc transporter genes underscore
the importance of micronutrient regulation in neuronal func-
tion, implicating zinc deficiency in ASD-related cognitive Author Contributions
impairments and epilepsy. Additionally, genetic imprinting
and hypomethylation processes have been linked to in- Raneem Nabil Halaweh is the sole author. The author read
creased ASD risk, particularly with advanced paternal age. and approved the final manuscript.
Overall, these findings underscore the intricate interplay be-
tween genetic predisposition and neurological development
in ASD. While advances in genomic technology have facili- Conflicts of Interest
tated the identification of specific genetic markers and path-
The author declares no conflicts of interest.
ways linked to ASD, the role of acquiring multiple genetic
mutations in one individual and its effect on symptom sever-
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