Increasing evidence suggests that autism is not a distinct
condition but a spectrum of disorders, which have in common
features that vary considerably in severity. The shape
and nature of the boundaries of this "autistic spectrum"
are unclear. Recent research indicates that autistic disorders
are caused indirectly by complex genetic influences. Genes
are non-deterministic risk factors, and a genetic predisposition-
which could be quite common in the general population-does
not necessarily manifest in overtly autistic behaviors.
The following are timely and critical questions about
the origins of autism:
- What have we learned about genes that influence the
risk of developing autism?
- How does genetic risk influence the functioning of
the brain?
- What correspondence is there between abnormal brain
functioning and observable autistic behaviors?
- Why doesn't everyone at genetic risk of autism become
autistic?
Gene discovery could be helped by two novel and complimentary
approaches:
- First, developing dimensional measures that can sensitively
capture the severity of autistic behaviors-no single
component of which is qualitatively distinct from normal
behavior.
- Second, discovering endophenotypes for autism, which
are subtle physiological or psychological abnormalities
that directly reflect genetic susceptibility, but which
are often not associated with overt behavioral disorder.
Progress in understanding the genetic risks associated
with autistic disorders has largely proceeded on the assumption
that a small number of genes is involved, and that affected
members of the same family share the same genetic risk.
Complementary investigations have assessed the role played
by rare and severe genetic anomalies in isolated individuals
or families. Neither approach has made direct links between
the nature of the genetic risk and abnormal functioning
of the autistic brain. Yet remarkable and consistent findings
are now being made that indicate the nature of functional
anomalies in the brains of autistic people. A primary
impairment lies in social intelligence, reflected in the
processing of social and emotional information. This deficit
is associated with some structural brain anomalies but,
more particularly, with abnormal activation of regions
collectively known as "the social brain."
Our previous work suggests specific genes on the X-chromosome,
which are expressed differently in males and females,
lower the threshold for the overt expression of genetic
vulnerability to autism conferred by genes elsewhere on
the genome. In collaboration with colleagues at the Whitehead
Center for Genome Research at MIT, we have recently identified
candidate genes that are potentially associated with the
development of social intelligence, because of their influence
on the functional integrity of the social brain. We are
close to piecing together, for the first time, a plausible
picture of how genetic variation influences social intelligence,
thereby illuminating the biological origins of the autistic
disorders.
