What causes Autism Spectrum Disorder (ASD)?

What Causes Autism Spectrum Disorder?

Autism Spectrum Disorder is primarily caused by genetic factors, with rare mutations having large effects being the most robustly identified genetic risks, though the disorder shows marked genetic heterogeneity with hundreds of genes potentially involved and heritability estimates between 70-90%. 1

Genetic Architecture

The genetic basis of ASD is complex and multifactorial:

• Rare genetic variants with large effect sizes are the most consistently identified causative factors, including copy number variations (CNVs), chromosomal abnormalities, and single-gene mutations 1
• Currently identifiable genetic causes account for only 10-40% of ASD cases, including diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects 2, 3
• Multiple genes interact to cause idiopathic autism, with whole-genome screens suggesting at least 10 genes are involved in causation 3
• Heritability is estimated at 70-90%, based on twin studies showing 60-92% concordance in monozygotic twins versus 0-10% in dizygotic twins 1, 3

Specific Genetic Mechanisms

Several genetic mechanisms contribute to ASD pathogenesis:

• Copy number variations affecting genes that regulate synaptogenesis and signaling pathways are major factors 4
• Chromosomal abnormalities at 15q11-q13 are fairly frequent, with a recognizable "chromosome 15 phenotype" in individuals with duplications 3
• The 7q31-q33 region (putative speech and language region) shows the strongest linkage to autism in genome-wide studies 3
• Mutations affect genes coding for cell adhesion molecules, voltage-gated ion channels, scaffolding proteins, and signaling pathways (PTEN and mTOR) 4

Known Genetic Syndromes

Specific genetic conditions account for a minority of cases:

• Tuberous sclerosis complex and fragile X syndrome together account for less than 10% of ASD cases 1, 3
• Rett syndrome is attributable to mutations in the MeCP2 gene in most affected individuals 3
• Single-gene disorders provide relevant models for understanding ASD pathophysiology despite their small contribution to overall prevalence 1

Environmental and Epigenetic Factors

While genetics predominate, other factors contribute:

• Environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections (rubella, cytomegalovirus) account for few cases 3
• Epigenetic modifications affecting DNA transcription and pre-natal/post-natal environmental exposures are precipitating factors 4
• Advanced maternal or paternal age and extremely premature birth (less than 26 weeks gestational age) are identified risk factors 5
• The interaction between genetic inheritance and environmental factors is influenced by epigenetics, contributing to phenotypic variability 2, 4

Recurrence Risk Patterns

Family studies demonstrate strong genetic influence:

• Sibling recurrence risk ranges from 2-19%, substantially higher than the general population prevalence of 2.2-2.3% 1, 6
• Sex bias in recurrence shows 7% risk if the first affected child is female versus 4% if male, consistent with multifactorial inheritance 1
• Multiple affected siblings increase risk dramatically, with 33-50% recurrence if two or more children have autism 1
• Female probands increase the risk that the next child will have ASD, supporting the presence of protective factors that reduce risk in females 1

Pathophysiological Mechanisms

Genetic factors lead to ASD through specific brain mechanisms:

• Genes contribute to behavior and cognition via their effects on brain structure and development 1
• Dysregulation of glutamatergic signaling and imbalance in excitatory:inhibitory pathways result from genetic mutations 4
• Glial cell activation and release of inflammatory mediators contribute to aberrant social behavior 4
• Synaptic transmission dysfunction and plasticity abnormalities result from mutations affecting synaptogenesis 4

Clinical Implications for Genetic Testing

Based on the genetic etiology, specific testing is warranted:

• Chromosomal microarray analysis is clinically indicated for all suspected cases of ASD 1
• Fragile X DNA testing should be performed in males and in females with consistent phenotype or relevant family history 1
• MECP2 sequencing is indicated in males with concerning clinical features (drooling, recurrent respiratory infections, hypotonia) and in all females with ASD 1
• PTEN gene sequencing should be performed in children with macrocephaly (head circumference >2.5 standard deviations above mean) 1

Important Caveats

Several points warrant emphasis:

• The male predominance (3:1 ratio) remains unexplained despite identification of some X-linked disorders, as male-to-male transmission rules out X-linkage as the prevailing mode 1, 3
• Wide phenotypic variability reflects interactions of multiple genes within an individual's genome and distinct gene combinations among affected individuals 2, 3
• Lower molecular diagnostic yield than anticipated given high heritability likely relates to multifactorial causation with etiological heterogeneity and complex gene-environment interplay 2
• Circumcision is not a risk factor for ASD and should not be considered in etiological evaluation 5