ASD Parent and Affected Child Exome Sequencing Display De Novo Mutation 23Are Genetic Mutations the Cause of Autism?
Since 1977 the belief has persisted that autism is a genetic and heritable
disease [8]. Both fathers of autism – Hans Asperger and Leo Kanner – thought
that autism ran in families and was heritable (not necessarily genetic). They
observed that the parents of autistic children were educated, elitists, and
imparted some version of autism to their offspring in an inherited fashion.
The most compelling evidence of the genetic origins of ASD is that maternal
twins show a significant concordance, according to some studies over 90%
concordance. According to this logic, both identical twins would show autism!
A thorough inspection of outcomes and claims that support a strong genetic
source of autism demonstrates that this interpretation is simply incorrect. It is
the erroneous product of methodological biases, flawed approximations,
and exaggerated media reports. Hallmayer et al. [42] in 2012 conducted one
of the most extensive discordant twin‐pair studies to date. They undertook
192 studies of twin pairs, and found that a high degree of ASD risk (~50%) in
maternal twins was the result of environmental factors, and that only a lesser
risk was the result of heritability. Of importance, they did not incorporate into
their analyses the single copy number variations (CNVs) and de novo muta
tions, as noted below. De novo mutations occur within the womb during ges
tation in the fetus only; thus, they are not inherited from a parent but caused
by something else following fetal development. This suggests that some
agents, such as chemicals, cause mutations during gestation in fetal brain
cells. We will consider this mechanism further shortly. We have devoted a
whole chapter to ASD and discordant twin‐pairs (see Chapter 6).
ASD Parent and Affected Child Exome Sequencing
Display De Novo Mutation
A recent report in exome sequencing has revealed several fundamental
aspects related to ASD. The exome is composed of exons of genes, which are
basic coding units and stands for “expressed genes”. There are approximately
30 million base pairs in the exome, which is about 1% of the total human
genome. Exome sequencing is carried out by choosing the exons using one of
a number of new solution based or array methods. The cDNA selected
through one of these processes is organized through massive parallel sequenc
ing, and by comparison with the reference genome SNPs are identified
[46,50–55] (Figure 1.13).
Exome sequencing analysis based on data regarding trios (two parents plus
an affected child, thus forming a trio) have found de novo mutations absent in
the parental exome but present in their children, presumably due to in utero