Decoding the genetic landscape of autism: A comprehensive review

Table 1 Genes implicated in autism spectrum disorder

No.	Gene symbol	Full gene name	Location	Function	Implication in ASD	Frequency in ASD patients
1	CHD8	Chromodomain helicase DNA binding protein 8	Chr. 14q11.	Crucial for chromatin remodeling and gene expression regulation	Regulates network of genes in ASD pathways. Disruption is linked to ASD, macrocephaly, gastrointestinal issues, facial dysmorphisms, social deficits, repetitive behaviors, and intellectual disability	0.2%-0.3%
2	CNTNAP2	Contactin-associated protein 2	Chr. 7q35	Essential for brain cell adhesion, synapse formation, and nerve signal transmission. Key role in language and cognition	Altered neural connectivity, language delays, social communication deficits, repetitive behaviors, intellectual disability	0.5%-1%
3	SHANK family	SH3 and multiple ankyrin repeat domains protein	SHANK: Chr. 19, SHANK: Chr. 11, SHANK3: Chr. 22q13.3	Postsynaptic scaffolding proteins are critical for glutamatergic synapse function. Mutations linked to ASD	Synaptic dysfunction affects the structural integrity of synapses, causing social deficits, repetitive behaviors, and intellectual disability	1%-2%
4	AVPR1A	Arginine vasopressin receptor 1A	Chr. 12q14-15	Regulates social behavior and communication	Variants linked to ASD impair social recognition, bonding, social cognition deficits, and repetitive behaviors	0.10%
5	OXTR	Oxytocin receptor	Chr. 3p26.2	Key in social cognition and emotional regulation	SNPs and deletions impact receptor function. Variations affect oxytocin binding, which is linked to ASD social deficits	0.1%-0.2%
6	DRD1, DRD2	Dopamine receptors D1 (DRD1), D2 (DRD2)	DRD1: Chr. 5q35.2, DRD2: Chr. 11q22-23	Crucial for reward processing, motivation, and social behaviors	Impact on synaptic transmission, neural circuits in social interaction. Repetitive behaviors, social deficits, and altered dopaminergic pathways	0.10%
7	DRD3	Dopamine receptor D3	Chr. 3q13	Modulates neural circuits related to movement, emotion, and cognition	Variants and CNVs impact dopamine signaling, potentially contributing to ASD features	0.10%
8	MECP2	Methyl-CpG-binding protein 2	Chr. Xq28	Regulates gene expression critical for neuronal development	Mutations associated with Rett syndrome and some cases of ASD	1%-2% in females with Rett syndrome
9	NRXN1	Neurexin 1	Chr. 2p16.3	Presynaptic cell adhesion molecule crucial for synapse formation	Mutations associated with social communication deficits and cognitive impairments in ASD	0.3%-1%
10	NRXN2	Neurexin 2	Chr. 11q13.1	Presynaptic cell adhesion molecule involved in synaptic transmission	Mutations associated with social communication difficulties and ASD traits	Rare, precise frequency unknown
11	NLGN4X	Neuroligin 4X	Chr. Xp22.32-p22.31	Postsynaptic cell adhesion protein is involved in synaptic function	Mutations associated with synaptic connectivity disruptions and ASD features	0.5% in males
12	NLGN4Y	Neuroligin 4Y	Chr. Yq11.221	Homolog of NLGN4X on the Y chromosome	Mutations contribute to synaptic dysfunction and ASD traits in males	Rare, precise frequency unknown
13	PTCHD1	Patched domain-containing protein 1	Chr. Xp22.11	Protein is crucial for brain neuronal development and synaptic function	Mutations associated with deficits in social communication, repetitive behaviors, and cognitive flexibility in ASD	0.5% in males
14	SLC6A4	Serotonin transporter	Chr. 17q11.2	Regulates serotonin levels in the brain	Variations linked to alterations in social behavior, repetitive behaviors, and sensory processing in ASD	0.1%-0.2%
15	DLG4	Discs large homolog 4	Chr. 17p13.1	Scaffolding protein is essential for organizing neurotransmitter receptors at synapses	Mutations associated with synaptic plasticity deficits and behavioral symptoms in ASD	Rare, precise frequency unknown
16	GABRG2	Gamma-2 subunit of GABA(A) receptor	Chr. 5q34	Mediates inhibitory neurotransmission in the CNS	Mutations associated with synaptic excitation/inhibition imbalance and ASD symptoms	0.10%
17	GRM7	Metabotropic glutamate receptor 7	Chr. 3p26.1	Modulates synaptic transmission and plasticity	Mutations associated with altered glutamatergic signaling and ASD traits	Rare, precise frequency unknown
18	BDNF	Brain-derived neurotrophic factor	Chr. 11p14.1	Promotes neuronal growth, survival, and synaptic plasticity	Mutations associated with cognitive and behavioral symptoms of ASD	Rare, precise frequency unknown
19	NRCAM	Neuronal cell adhesion molecule	Chr. 7q31.1	Involved in synaptic plasticity and neural connectivity	Mutations associated with altered neural circuitry and behavioral traits in ASD	Rare, precise frequency unknown
20	HTR2A	Serotonin receptor 2A	Chr. 13q14.2	Regulates serotonin signaling pathways in the brain	Mutations associated with social behavior deficits and cognitive impairments in ASD	Rare, precise frequency unknown
21	CX3CR1	Chemokine receptor 1	Chr. 3p22.2	Involved in brain immune response and neuroinflammatory processes	Variants associated with microglial dysfunction and synaptic connectivity issues in ASD	Rare, precise frequency unknown
22	CHRNA7	Alpha-7 nicotinic acetylcholine receptor	Chr. 15q13.3	Integral to cholinergic signaling in the CNS	Mutations associated with cognitive deficits, social impairments, and ASD symptoms	Rare, precise frequency unknown
23	GRIN2A	GluN2A subunit of NMDA receptor	Chr. 16p13.2	Essential for synaptic plasticity and learning	Mutations associated with cognitive impairments, seizures, and ASD features	Rare, precise frequency unknown
24	PTGS2	Prostaglandin-endoperoxide synthase 2	Chr. 1q31.1	Synthesizes prostaglandins involved in inflammation and immune responses	Potential role in immune dysregulation related to ASD; further research needed	Rare, precise frequency unknown
25	REELN	Reelin	Chr. 7q22	Guides neuronal migration and synaptic plasticity during brain development	Rare mutations associated with altered neuronal migration and synaptic connectivity in ASD	0.1%-0.2%
26	FOXP2	Forkhead box P2	Chr. 7q31.1	Important for language development and speech production	Rare mutations linked to speech and language deficits in individuals with ASD	Rare, precise frequency unknown
27	SNAP25	Synaptosome associated protein 25	Chr. 20p12.2	Facilitates neurotransmitter release at synapses	Rare genetic variants implicated in synaptic dysregulation in ASD	Rare, precise frequency unknown
28	CACNA1G	Calcium voltage-gated channel subunit alpha1 G	Chr. 17q21.33	Part of voltage-gated calcium channels regulating neuronal excitability and synaptic plasticity	Rare mutations associated with altered neural connectivity and behavior in ASD	Rare, precise frequency unknown
29	GABRA5	Gamma-aminobutyric acid type A receptor alpha5 subunit	Chr. 15q12	Subunit of GABA-A receptor critical for inhibitory neurotransmission	Rare variants linked to disrupted GABAergic signaling in ASD	Rare, precise frequency unknown
30	GRIN2B	Glutamate ionotropic receptor NMDA type subunit 2B	Chr. 12p13.1	It is a subunit of NMDA receptor involved in synaptic plasticity and excitatory neurotransmission	Rare mutations associated with altered synaptic signaling pathways in ASD	Rare, precise frequency unknown
31	GRIK2	Glutamate ionotropic receptor kainate type subunit 2	Chr. 6q16.3	Subunit of kainate receptor modulating synaptic transmission and plasticity	Rare genetic variants implicated in synaptic dysfunction and behavioral traits of ASD	Rare, precise frequency unknown
32	HOMER1	Homer protein homolog 1	Chr. 5q14.1	Postsynaptic density protein is involved in synaptic signaling and plasticity	Rare mutations linked to synaptic dysfunction and behavioral traits of ASD	Rare, precise frequency unknown

The frequency values provided are approximate and can vary depending on the specific study or population examined. Some genes have "Rare, precise frequency unknown," indicating that while they are implicated in autism spectrum disorder, their mutation frequency is less clearly defined. ASD: Autism spectrum disorder; CNS: Central nervous system; CNV: Copy number variation; NMDA receptor: N-methyl-D-aspartate receptor; SNPs: Single nucleotide polymorphisms.

Table 2 The differences in autism symptomology and related factors between males and females

Aspect	Males with ASD	Females with ASD
Prevalence	Higher prevalence, male-to-female ratio 1.33:1 to 15.7:1	Lower prevalence
Behavioral manifestation	More externalizing behaviors (aggression, repetitive movements, hyperactivity)	More internalizing behaviors (anxiety, depression)
Cognitive impairments	Less pronounced cognitive impairments	More pronounced cognitive impairments, with a male-to-female ratio nearing 1:1 among those with severe intellectual disabilities
Diagnostic bias	More likely to be diagnosed due to overt behaviors	Less likely to be diagnosed unless severe impairment is present due to less disruptive behaviors
Genetic load	Lower genetic load	Higher genetic load in affected females and unaffected female relatives compared to males
Compensation and masking strategies	Less frequent use	More frequent use
Clinical criteria meeting	More likely to meet clinical criteria for ASD given the same genetic risk	Less likely to meet clinical criteria, may exhibit related issues such as anxiety
Sex chromosome influence	Y chromosome may pose a risk	The second X chromosome may offer protection, as indicated by higher ASD rates in Turner syndrome (XO) and 47, XYY syndrome
Hormonal influence	Differences in the vasopressinergic system, higher fetal testosterone levels associated with ASD traits	Potential protection from the second X chromosome, hormonal influences not as clearly defined
Camouflage strategies	Less frequent use	More frequent use to mask symptoms
Research and treatment	Focused mainly on males	Lack of hypothesis-driven treatment studies targeting females

This table highlights the key differences in the manifestation, diagnosis, and underlying biological mechanisms of autism spectrum disorder between males and females. Understanding these differences is essential for improving diagnostic criteria and developing gender-specific treatments. ASD: Autism spectrum disorder.

Table 3 Comparison between the different gene-environment interaction models in the context of autism spectrum disorder

Model	Key concept	Description	Examples
Diathesis-stress model	Genetic vulnerability plus environmental stressors trigger ASD	Inherited genetic predispositions (diatheses) interact with environmental stressors to manifest ASD	Prenatal stress, maternal infections, or toxin exposure in genetically predisposed individuals lead to the development of ASD
Differential susceptibility model	Genetic variants make individuals more responsive to environmental influences, both positive and negative	Certain genetic profiles heighten sensitivity to environmental conditions, affecting ASD risk and response to interventions	Genetically susceptible children may develop ASD with prenatal toxin exposure but show improvement with enriched early learning environments
Biological sensitivity to context model	Genetic variations influence sensitivity to environmental contexts	Some individuals have heightened biological reactivity to environmental stimuli due to their genetic makeup, impacting neurodevelopment and ASD risk	Children with specific genetic profiles may have increased stress responses to environmental toxins or benefit more from supportive caregiving
Gene-environment correlation model	Genetic predispositions influence exposure to certain environments	Genetic factors shape individuals' environments, through passive, evocative, or active correlations	Parents with ASD traits create environments affecting child development (passive); a child’s social difficulties lead to isolation (evocative); a child avoids noisy places (active)
Epigenetic models	Environmental factors modify gene expression through epigenetic mechanisms	Environmental influences like nutrition, toxins, or stress-induced changes in gene expression via DNA methylation or histone modification affect neurodevelopment and ASD risk	Prenatal air pollution exposure causes DNA methylation changes in neurodevelopmental genes, influencing ASD risk
Integrative models	Combines genetic, environmental, and epigenetic factors for a holistic understanding of ASD risk	Integrates multiple frameworks, considering genetic vulnerabilities, environmental exposures, and epigenetic mechanisms in ASD development	Interaction of genetic neuroinflammation susceptibility with prenatal maternal infections leads to epigenetic changes and increased ASD risk

This table provides a comparative overview of the key concepts, descriptions, and examples of how each model explains the interaction between genetic and environmental factors in autism spectrum disorder development. ASD: Autism spectrum disorder.