What causes Autism Spectrum Disorder (ASD)?

What Causes Autism Spectrum Disorder (ASD)?

Autism spectrum disorder (ASD) is primarily caused by genetic factors that affect brain development, with multiple genes and rare genetic mutations playing the most significant role in its etiology. 1

Genetic Factors

• Genetic factors are the predominant causative determinants of autism, with heritability estimated at 70-90% 1, 2
• Twin studies show 60% concordance for classic autism in monozygotic twins versus 0% in dizygotic twins, increasing to 92% in monozygotic twins when considering broader autism phenotypes 3
• Multiple interacting genes are involved, with data suggesting interactions of at least 10 genes in the causation of autism 3
• The most robustly identified genetic risks for ASD are rare mutations with large effect 1
• Chromosomal abnormalities, particularly at the 15q11-q13 locus, are frequently found in people with autism 3
• Single gene disorders account for a small percentage of cases:
  • Fragile X syndrome (found in approximately 0.5% of children with ASD) 1
  • MECP2 mutations (found in approximately 4% of girls with nonsyndromic ASD) 1
  • PTEN mutations (associated with ASD and macrocephaly) 1

Inheritance Patterns

• Recurrence risk in siblings of affected children is approximately 6-20%, much higher than the general population prevalence 1
• Risk varies considerably depending on family composition:
  • A mother with two boys with ASD has a 32% risk of the next male child being autistic 1
  • In a family with only one male autistic child, the risk for the next female child is close to 10% 1
• Males are affected 3-4 times more frequently than females, with the most likely explanation being protective factors that reduce ASD risk in females 1

Environmental Factors

• Environmental factors account for a smaller proportion of ASD risk compared to genetic factors 3
• Potential environmental risk factors include:
  • Advanced maternal or paternal age 1
  • Extremely premature birth (<26 weeks gestational age) 1
  • Closer spacing of pregnancies 1
  • Prenatal and perinatal complications 4
  • Parental psychopathology and family/interpersonal relationship factors 4
• Despite past concerns, studies have not supported a link between vaccines (measles-mumps-rubella) or thimerosal (a mercury-containing preservative) and autism 1, 3

Neurobiological Findings

• EEG abnormalities and seizure disorders are observed in 20-25% of individuals with autism 1
• Structural brain differences include:
  • Overall brain size increase in autism 1
  • Aberrations in white matter tract development 1
  • Abnormalities within the limbic system found in postmortem studies 1
• Functional MRI studies have identified difficulties in tasks involving social and affective judgments and differences in processing facial and non-facial stimuli 1
• Neurochemical findings include elevation of peripheral serotonin levels 1

Clinical Implications

• Genetic testing is clinically indicated for all suspected cases of ASD 1
• Recommended genetic testing includes:
  • Chromosomal microarray analysis 1
  • DNA testing for fragile X in males 1
  • MECP2 sequencing in females 1
  • PTEN gene sequence analysis for individuals with macrocephaly 1
• Early identification and intervention are crucial as they increase effectiveness of treatment 5
• Children with dysmorphic features, congenital anomalies, intellectual disability, or family members with developmental disorders benefit most from extensive medical testing and genetic consultation 3

Important Caveats

• The reported increase in ASD prevalence (from 1.1% in 2008 to 2.3% in 2018) is likely due to changes in diagnostic criteria, improved screening, and increased awareness rather than new environmental influences 3, 5
• No specific biomarkers for ASD have been identified 5
• ASD is frequently associated with comorbidities including depression (20%), anxiety (11%), sleep difficulties (13%), and epilepsy (21% with co-occurring intellectual disability) 5
• The wide phenotypic variability of ASD likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affected 3