The Genetics of Autism
Contrary to popular belief (and Jenny McCarthy), autism is the most genetic and inheritable of all neurodevelopmental disorders. Identical twins have >80% chance of shared diagnosis, versus a much lower ~10% chance in fraternal twins, a classic indication of underlying common genetic cause.
What is autism? Classical autism is part of a broader group of autism spectrum disorders (ASD) characterized by (i) impaired social communication and interaction, (ii) absence or delay in language and (iii) restricted, repetitive behavior. These features vary hugely, from severe intellectual disability to mild personality traits. Intellectual delays occur in 30-60%, and 30% also suffer seizures. Current rates of diagnosis are 1 in 88 children. This is partly due to a broadening of the diagnosis but could also reflect impact of changing environment on genetic susceptibility.
Monogenic cases of autism are known as syndromes. About 10% of children diagnosed with ASD have mutations in a single gene. The most common is Fragile X syndrome (FXS), which accounts for 5% of autism cases with as many as 50% of individuals with FXS meeting criteria for autistic disorder. Other syndromes that present with ASD are Tuberous Sclerosis, Retts, and Neurofibromatosis. Although the primary diagnosis is not ASD, the symptoms include ASD.
Polygenic disorders are caused by additive effects of multiple genes. Because inheritance patterns of autism are not Mendelian, it was initially thought to be polygenic, like traits of hypertension, height or skin color. Austism superficially fits this definition because of the continuous spectrum of characteristics. But, it’s a lot more complex because no single gene appears to account for more than 1% of the non-syndromic cases.
Heterogenic disorders occur when mutations at any of a number of different genes can give rise to the same phenotype. In autism, many of the mutations are unique, rare and arise de novo, not being found in parents or recent ancestry. Most mutations occur on only one allele (one of two copies of the gene). Many are copy number variations, affecting gene dosage, caused by insertions and deletions in the chromosome. The emerging theory is that many different mutations converge on a common function: synaptic transmission.
The synapse: Information transfer occurs at the synapse or junction between neurons. The first synapses in human cortex appear 40 days after conception. The most dramatic change takes place around birth. During the first three years of life, more synaptic contacts are formed, but only some will be stabilized. Many genes implicated in autism (image) function at the synapse, and the timing of appearance of autistic characteristics coincides with synapse maturation.
REF: Autism and Brain Development. Walsh et al., Cell (free read) http://goo.gl/hkbsC