What we know: Genetics

Iker Spozio


Genes play a major role in autism. First, the concordance among identical twins is 90 percent in some studies. Second, several monogenic syndromes such as fragile X syndrome are associated with traits of autism. Third, the burden of loss-of-function mutations is greater in idiopathic autism than in unaffected individuals.

However, the genetic landscape of autism is far from clear.

What we know

  1. Highly penetrant, loss-of-function de novo mutations, including copy number variants (CNVs), single nucleotide variants and insertion and deletion mutations, have been identified in trio and quad families (a quad family consists of two biological parents, the child with autism and one unaffected sibling) in the Simons Simplex Collection and other cohorts.
  2. Recurrence is the principal criterion for accepting a de novo variant as a true autism risk factor.
  3. De novo risk variants are individually rare (each accounting for less than 1 percent of cases), but together they may account for more than 25 percent of autism cases. It is likely that this proportion will rise as researchers examine larger cohorts and implicate missense mutations in the disorder.
  4. Girls with autism tend to have larger CNVs than boys do, suggesting that females have compensatory mechanisms that may relate to more robust social behaviors.
  5. To date, most de novo variants have been found in individuals with low intelligence quotients, but the causal relationship between intelligence and autism is unclear.
  6. About 30 percent of children with idiopathic intellectual disability or monogenic syndromes, such as fragile X, tuberous sclerosis, neurofibromatosis, Rett syndrome and Timothy syndrome (all of which are associated with intellectual disability), exhibit traits of autism.
  7. There is significant overlap between de novo variants found in the Simons Simplex Collection and the 849 genes regulated by fragile X mental retardation protein.
  8. Dose-dependent effects are evident when comparing deletions and duplications at chromosomal regions 16p11.2, 7q11.23 and 22q11.2.
  9. Analyses of gene networks in autism point to variants in genes involved in synaptic function and plasticity, neuronal development, voltage-gated ion channels, neuroimmunology and the regulation of chromatin structure.
  10. Younger siblings of children with autism have a relatively high probability of developing autism (20 percent in some studies), consistent with inherited risk factors or with germ-line mosaicism.

What is next?

  1. Can additional de novo variants be discovered and suspect variants validated by targeted DNA sequencing or by whole-genome sequencing in large cohorts (5,000–10,000 individuals)?
  2. Can telephone interviews be validated to acquire detailed phenotypic data in the same cohorts as are used for genetic analyses?
  3. Do normal- and high-intelligence individuals with autism have novel or less severe genetic variants?
  4. Are there correlations between autism-risk genes and particular autism traits?
  5. Can somatic mutations in brain cells be identified using autopsy material or re-differentiated pluripotent stem cells?
  6. Can sex–specific factors or patterns of gene expression be identified?
  7. Are there genes and epigenetic mechanisms that modify the expression of known risk variants (including allele-specific inactivation)? Recent studies of CNVs are consistent with a multi-hit etiology of autism.
  8. Can analyses of gene networks be refined to take into account changes in gene expression over time in various regions of the brain?
  9. What is the clinical spectrum of individuals who bear the same autism genetic risk variant (for instance, 16p11.2 microdeletion)?
  10. Can high-throughput functional assays be devised to screen several hundred candidate genes?
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