What are the biological factors in Autism Spectrum Disorder (ASD)?

Biological Factors in Autism Spectrum Disorder

The biological basis of autism spectrum disorder is fundamentally genetic, with rare mutations having large effects being the most robustly identified risk factors, though the disorder involves complex interactions between hundreds of genes, aberrant brain development, and neurobiological mechanisms affecting synaptic connectivity and neural circuitry. 1

Genetic Architecture

Genetic factors are the most significant contributors to ASD, with heritability estimates of 70-90% based on twin studies showing 60-92% concordance in monozygotic twins versus 0-10% in dizygotic twins. 2, 3

Types of Genetic Variants

• Rare mutations with large effect sizes represent the most consistently identified causative factors, including copy number variations (CNVs), chromosomal abnormalities, and single-gene mutations 1, 3
• Common genetic variations contribute to most of the population-level genetic risk, with each variant having small individual effects but acting collectively 4
• De novo mutations (spontaneous mutations not inherited from parents) play a substantial role, particularly in severe phenotypes 4, 5

Specific Genetic Syndromes and Mutations

The following monogenic disorders and genetic abnormalities are associated with high ASD risk 1:

Epilepsy-associated mutations:

• Tuberous sclerosis complex (TSC1 and TSC2)
• Rett syndrome (MECP2)
• CNTNAP2
• Fragile X syndrome
• 15q11.1-q13.3 duplication
• 16p11.2 deletion
• 22q11.2 deletion
• Phelan-McDermid syndrome (SHANK3, 22q13.3 deletion)
• Angelman syndrome (UBE3A) 1

Motor impairment-associated mutations:

• AUTS2 (motor delay)
• NRXN1 deletion (hypotonia)
• 2q23.1 deletion and duplication (hypotonia and motor delay) 1

Clinical Genetic Testing Recommendations

Chromosomal microarray analysis is warranted and clinically indicated for all suspected cases of ASD, with a diagnostic yield of approximately 40%. 1, 2, 3

Additional targeted testing should include 3:

• Fragile X DNA testing in males and females with consistent phenotype
• MECP2 sequencing in males with concerning features and all females with ASD
• PTEN gene sequencing in children with macrocephaly (head circumference >2.5 standard deviations above mean)

Neurobiological Mechanisms

Brain Development Abnormalities

Genes contribute to behavior and cognition in ASD via their effects on brain structure and development, with many ASD-associated genes playing roles in neuronal proliferation, growth, organization, and synaptogenesis. 1, 6

• Brain size increases and aberrations in white matter tract development have been consistently observed in structural imaging studies 2
• Aberrant neuronal connectivity represents a core pathological feature, with excessive beta activity noted in some cases 1
• Synaptic plasticity disorders result in an imbalance of excitation and inhibition, which may explain the overlap between ASD and epilepsy 1

Neurochemical Findings

• Elevated peripheral serotonin levels represent one of the most frequently replicated neurochemical findings in autism 2
• Functional MRI studies identify difficulties in tasks involving social and affective judgments 2
• Neuropsychological correlates include impairments in executive functioning, weak central coherence, and deficits in theory-of-mind tasks 2

Sex-Related Biological Factors

The most parsimonious explanation for the 3-4.5:1 male predominance in ASD involves protective factors that reduce risk in females, supported by increased ASD rates in Turner syndrome (XO) and 47,XYY syndrome. 1, 2, 7

• The Y chromosome may act as a risk factor, or a second X chromosome may be protective 1, 7
• Fetal testosterone levels correlate with systematizing traits, social impairments, and reduced empathy 1
• Decreased second digit-to-fourth digit ratio (indicating increased fetal testosterone exposure) is associated with ASD diagnosis 2
• Female probands increase recurrence risk in siblings, suggesting females require a higher genetic burden to manifest ASD 1, 2, 3

Familial Risk Patterns

Sibling recurrence risk varies considerably based on family composition, ranging from 6% on average to as high as 32% for mothers with two affected boys having another male child. 1, 2

• Multiple affected siblings increase risk dramatically to 33-50% 3
• Female probands confer 7% risk versus 4% if the first affected child is male 3
• High rates of learning/language problems and social disability occur in family members of individuals with ASD 2

Prenatal and Perinatal Biological Factors

• Advanced maternal and paternal age significantly increases ASD risk 2, 3
• Extremely premature birth (<26 weeks gestational age) increases risk 2, 3
• Closer spacing of pregnancies is associated with increased risk 2

Environmental-Biological Interactions

Environmental chemicals may target autism-related genes, with the prenatal period representing a particularly sensitive window when the developing brain is susceptible to disruptions. 2

• Pesticides, heavy metals, bisphenol A (BPA), and phthalates have been implicated 2
• Chlorpyrifos, lead, and polychlorinated biphenyls (PCBs) warrant systematic review 2
• Valproic acid exposure has been associated with ASD development 6

Neurological Comorbidities with Biological Basis

Specific genetic mutations are associated with both ASD and neurological comorbidities, suggesting shared pathophysiological mechanisms. 1

• Epilepsy occurs in 5-46% of children with ASD, with epileptiform abnormalities in up to 60% 1, 2
• Motor impairments including delayed milestones, apraxia, hypotonia, and malcoordination are common 1, 2
• Sleep disturbances affect 53-78% of individuals with ASD 1, 2

Mechanistic Relationship

ASD and epilepsy can be conceptualized through two pathways 1:

1. A genetic variant causes aberrant brain development leading to seizures, which then impair early cognitive and social development
2. ASD and epilepsy represent two sequelae of a common process of aberrant neurodevelopment from shared genetic mutations

Important Clinical Caveats

• Genetic heterogeneity is substantial, with hundreds of genes potentially involved and variable penetrance 4, 5
• The dramatic rise in ASD prevalence (from 1 in 150 in 2002 to 1 in 59 in 2014) cannot be fully explained by genetics or diagnostic changes alone, suggesting environmental contributions 2
• Understanding genotype-phenotype relationships requires population-level genetic screening tied to longitudinal phenotype data 1
• Different risk genes converge on common mechanisms such as gene regulation and synaptic connectivity 4