De Novo Mutations 157CNVs, the very small gain or loss of genomic DNA (meaning there is an extra
fragment of DNA found in the ASD child or small DNA fragments are lost).
Usually, these DNA fragments are relatively small (i.e., <400 kb of DNA) that
either disappear or emerge in an offspring. De novo CNVs are present in 4–7%
of ASD children as compared with 1–2% in unaffected siblings or normal con-
trols. Other than in ASD, larger fragments of DNA CNVs (>400 kb) affecting
genes are present in 15% of patients with developmental delay or intellectual
disability. The majority of these CNVs are personal to each individual, but
some are repeatedly observed in independent patients, suggesting that these
are rather random DNA mutations that appear in a child due to exposure to
some harmful chemical during the fetal development. There have been 2,350
different CNVs found in ASD children, suggesting that these are chemically
induced mutations that are present in the ASD children but mostly absent in
the parents of these children [2]. Some studies have found no real differences
in CNVs between ASD and controls [50]. The studies have also indicated that
de novo CNVs identified in patients with ASD are most likely altering genes
associated with synaptic functions. For example, Carreira and colleagues [51]
analyzed 2,446 ASD‐affected families and confirmed an excess of genetic dele-
tions and duplications in affected versus control groups that were statistically
highly significant (1.41‐fold, p = 1.0×10−5).
It is believed by many that CNVs increase the risk of having ASD in 5–10% of
individuals. But, we believe that these CNVs are the result of mutations that are
induced by the chemicals that a fetus is exposed to during prenatal develop-
ment. Furthermore, we predict that there will be many thousands of mutations
discovered as technological advancements able to identify slight variations in
noncoding genes. CNVs do not necessarily mean “genetic defects” and are
found in all of us as a natural variation phenomenon [51].
Few of the advanced technologies that are coming to light are whole exome
or genome sequencing studies of the mRNAs or DNAs of ASD patients. One
can identify even a single nucleotide variant or SNV. In particular, numerous
de novo SNVs have been identified using whole exome sequencing of individu-
als with sporadic ASD. Among them, several disruptive mutations associated
with sporadic ASD were reported, however, the genetic mutations in these
genes account for only a small proportion of all cases. Several thousand SNVs
have been found and the numbers will increase. Unfortunately, the functions of
most candidate ASD‐associated genes, as well as the biological significance of
the identified mutations in the central nervous system, remain unknown
despite extensive bioinformatics resources. Accordingly, although the precise
functional analysis of each disease‐associated gene and its mutation is impor-
tant for understanding the etiology of ASDs, it is not easy to assign priorities to
essentially thousands of mutations that are found in ASD children for further
detailed biological analysis. We argue that these are mutations induced by syn-
thetic chemicals and may or may not have any real direct function.