Myth of the Genetic Origin of Autism 69constraints on deleterious variation (meaning if too much and too many
changes are made in the genes the fetus would die in the womb, so called nega-
tive or purifying selection), whereas rare variation can be associated with a
much wider range of effect sizes. Chaste and Leboyer [50] looked at common
variation in ASD to answer questions about relationships between clinical and
genetic heterogeneity. Enormous advances have been made in understanding
the genomic architecture of ASD, including the role of common and rare vari-
ation. There is compelling evidence from multiple studies that common varia-
tion represents the major proportion of the genetic risk for ASD [49,50].
However, no SNP has been reliably associated with ASD to date because of
small effect sizes. Until studies include many thousands of cases, it is exceed-
ingly unlikely that many replicated common variation findings will be made in
ASD. There has been much more success with gene discovery in ASD when
focusing on rare variation. This increased success is due partly to the fact that
there is a significant amount of de novo mutation in ASD: with de novo muta-
tion being quite rare, even a few cases with de novo deleterious variation in a
given gene are sufficient to provide statistically significant support for that
gene in ASD [50]. Although the effect size for discoverable rare variation is
higher than that of common variation, the total variance explained by rare vari-
ation is quite low. Gaugler et al. [51] showed that within a given family with
ASD, a rare de novo copy number variant (CNV) or single nucleotide variant
can often be the difference between an ASD diagnosis or no ASD diagnosis;
however, there must be a “genetic background” in the family, defined by multi-
ple inherited SNPs and other genetic variation, that is a critical part of the
architecture in that family. In other words, there appears to be risk in the family
in most cases in the form of a multiplicity of common variation, and higher risk
rare variation pushes an individual in that family over a liability threshold to
manifest with neurodevelopmental disorders. This model can explain why risk
of family recurrence is high in ASD, while, at the same time, affected sibling or
relative pairs within a family may have different rare risk variants, as first
shown with CNV and, more recently, with single nucleotide variant [52,53].
Similar findings have been observed in studies of rare variation. Several rare
ASD risk genes have been found in recent whole exome sequencing studies
that examined >20,000 samples across approximately 4,000 cases of ASD [54–56].
Many recurrent CNVs have been linked to multiple phenotypes, such as with
DiGeorge/velocardiofacial syndrome (22q11 deletion syndrome), which has
been linked not only to autism, but also to epilepsy, schizophrenia, and con-
genital heart disease. In fact, as an example, chromatin remodeling genes
appear to play a significant role in both ASD and congenital heart disease [57)].
Rare risk genes and CNV linked to intellectual disability have also been asso-
ciated with ASD [54–56]. However, controversy persists in classification of
ASD with and without intellectual disability, especially when social impair-
ments result from other causes, such as a lack of social drive (Kanner autism)