T Connecting Genes to Brain in the Autism Spectrum Disorders

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T Connecting Genes to Brain in the Autism Spectrum Disorders
Connecting Genes to Brain
in the Autism Spectrum Disorders
Brett S. Abrahams, PhD; Daniel H. Geschwind, MD, PhD
he autism spectrum disorders (ASDs) are a complex group of neuropsychiatric conditions involving language, social communication, and mental flexibility. Here, we attempt to place recent genetic advances within a developmental and anatomical context. Recent progress in identifying ASD candidate genes supports involvement of multiple
brain regions, including the frontal lobes, anterior temporal lobes, caudate, and cerebellum. Understanding genetic data within an anatomical context will be critical to explain how individual
risk factors operate to shape phenotypic presentation in patients.
Arch Neurol. 2010;67(4):395-399
The understanding and treatment of neurodevelopmental disorders pose many
challenges to biomedicine, not the least of
which is that many of the most common
clinical diagnoses such as dyslexia, attention-deficit/hyperactivity disorder, or generalized intellectual disability are not defined on the basis of etiology but rather
with regard to behavior and cognition. Perhaps nowhere is this more salient than in
the ASDs, defined by clinical impairment
in language, social interaction, and behavioral flexibility, all prior to 3 years of age.
Variation in an ever-growing number of
genes appears to modulate risk and presentation,1 and thus it is perhaps not surprising that multiple brain structures have
been implicated in these disorders. Stepping back, however, emerging data support the notion that the ASDs can be conceptualized in terms of multiple genetic
etiologies that disrupt the development and
function of brain circuits mediating social cognition and language.2
The identification of genetic risk factors for ASDs has proceeded by multiple
parallel and complementary approaches
(Figure). Early insights came from the recognition that individuals with a handful
of single-gene syndromes (eg, fragile X synAuthor Affiliations: Programs in Neurogenetics and Neurobehavioral Genetics,
Neurology Department, and Semel Institute for Neuroscience and Behavior,
David Geffen School of Medicine, University of California, Los Angeles.
drome, tuberous sclerosis, and Joubert syndrome) show features of the ASDs at frequencies much higher than expected.
Cytogenetic studies identified recurrent,
maternally inherited duplications of chromosome 15q11-13, which along with other
rare chromosomal abnormalities remains an
important cause of the ASDs.3 More recently, individual genes of major effect (eg,
NLGN4, NRXN1, and SHANK3) have been
identified by resequencing or array-based
methods. Although collectively accounting for an estimated 15% of cases, variants at these and other loci are present in
no more than 1% to 2% of children with
an ASD. Specificity is also an issue here,
with such variants having been observed
not only in individuals with an ASD diagnosis but also in patients with related conditions such as nonsyndromic mental retardation.4
In addition to rare alleles of major effect,
association studies have demonstrated involvement of numerous common variants with smaller effects.5 Although independently replicated linkage findings are
the exception rather than the rule, such
studies have proven helpful in the establishment of the veracity of key loci, including those on chromosomes 7q and 17q.
Together, these studies underscore the
commonly held notion that ASD risk is
complex and is likely to involve many dif-
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Cytogenetic analyses
Recognition of elevated ASD risk in specific genetic disorders
Diagnostic refinement for the ASDs (ADOS, ADI-R)
Association studies (candidate genes)
Whole-genome linkage studies
Resequencing (candidate genes)
CNV analysis (detection and characterization)
Whole-genome association studies (SNP and CNV)
Resequencing (whole exome via pull-down or whole genome)
Figure. Methodological changes have accelerated progress in autism spectrum disorder (ASD) genetics. The collection of large cohorts via international
collaboration together with array-based technologies permitting genome-wide interrogation of genetic variation has resulted in major advances. Similar progress
will come from massively parallel sequencing of partial and whole genomes. Although such experiments are soon likely to become routine, interpretation of
results, particularly in the context of diverse phenotype data, will require massive computational infrastructure. ADOS indicates Autism Diagnostic Observation
Schedule; ADI-R, Autism Diagnostic Interview–Revised; CNV, copy number variation; and SNP, single-nucleotide polymorphism.
ferent genes and even distinct modes of inheritance among
individuals. Large cohorts with 10 000 or more wellphenotyped cases, family members, and unrelated control subjects will be required to fully explore the genetic
architecture of the ASDs.
As the list of established genetic risk factors grows, an
important challenge will be to understand the manner
by which individual genes shape the development and
function of regions and circuits affected in disease. Until recently, disorders like fragile X syndrome, Timothy
syndrome, tuberous sclerosis, and Smith-Lemli-Opitz syndrome were not considered by many to be bona fide causes
of autism but rather clinical peculiarities only tangentially related to the true issues at hand. Recent work demonstrating that no individual cause of autism accounts
for more than 1% to 2% of cases, however, has made the
importance of these and other ASD-related syndromes
more apparent. Moreover, because these syndromic cases
are genetically more homogeneous than corresponding
“idiopathic” ASDs, it is reasonable to posit that study of
these genetic syndromes, where careful contrasts can be
made between individuals with defined genotypes, will
provide important insights. As summarized here, study
of different ASD-related syndromes and monogenic risk
factors supports shared involvement of frontal and temporal neocortex, caudate, and cerebellum.
Accelerated early head growth has also been observed
among individuals with fragile X syndrome,6 similar to results from idiopathic ASD cases (see later). Although such
effects were observed in all mutation carriers relative to
control subjects, they were seen a full year earlier in individuals with fragile X syndrome who also carry an ASD
diagnosis. Structural imaging of fragile X syndrome cases
and controls has also found abnormalities in the caudate
(increased), lateral ventricles (increased), and posterior vermis of the cerebellum (reduced).7 Functional magnetic resonance imaging evidence also provides support for involvement of frontostriatal circuitry among cases.8 Dendritic
spine maturation is also abnormal in cases, appearing long
and thin in cases compared with controls, consistent with
an immature phenotype.9,10
Similar results emerge from an analysis of Rett syndrome cases, despite being complicated by behavioral regression, progressive atrophy, and a global (as opposed
to regional) hypoplasia.11 A positive relationship between patient age and cerebellar atrophy, however, points
to this structure as an important mediator of disease progression. Similarly, frontal and temporal cortices—as well
as the caudate—appear subject to the greatest regional
reductions in gray matter volume.12 Frontal, motor, and
temporal cortices are also implicated by neuropathological investigations, as pyramidal neurons within these regions show reduced dendritic arborization.13,14
Although less is known about Joubert syndrome, which
unlike fragile X syndrome can result from mutations in at
least 9 identified genes at 10 or more loci, available data
suggest that pathological findings in cases are not without parallels. Affected individuals present with hypoplasia of the cerebellar vermis and the molar tooth sign, visible in transverse section as an enlargement of the cerebellar
peduncles and associated interpeduncular cistern along with
a reduction in the diameter of the midbrain. Examination
of phenotypically discordant monozygotic twins makes an
important contribution to the understanding of these features—although the molar tooth sign was present in both
girls, only the severely affected sibling showed cerebellar
hypoplasia.15 Observation of polymicrogyria in some cases
with mutations in the AHI1 gene16 suggests that cortical
dysgenesis may also be involved in disease pathogenesis,
although this feature is not consistent among all families
even when considering only mutations in this gene.17
Cortical dysplasia and abnormalities in neuronal migration in patients homozygous for a frameshift mutation within the CNTNAP2 gene18 likewise provide support for an early developmental insult, particularly in the
frontal and temporal neocortex, in this ASD-related syndrome. All subjects homozygous for the frameshift mutation had seizures and language regression, and twothirds of these also met Diagnostic and Statistical Manual
of Mental Disorders (Fourth Edition)19 criteria for an ASD.
Examination of resected tissue from temporal cortex
showed cortical thickening, abnormal neuronal organization and morphology, and ectopic neurons in subcortical white matter. Of particular interest and potentially
complicating the use of model systems to study involve-
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ment of this gene in disease, the human transcript is highly
restricted to cortico-striato-thalamic circuitry known to
subserve executive function and language, whereas expression in mouse and rat is relatively unremarkable
within the telencephalon.20 Consistent with the use of
zebra finch as a model system, recent work demonstrates enrichment of Cntnap2 in song nuclei essential for
vocal learning.21 Like the sexual dimorphic behavior itself, enrichment of messenger RNA in song nuclei was
male specific.
The manner by which tuberous sclerosis affects neurodevelopment and brain function is complicated by the
variability in localization, number, and size of the diseaseassociated growths (tubers) that accumulate in the developing brain.22 Consistent with pathological findings
in other syndromes, however, a comparison of IQmatched patients with tuberous sclerosis with and without a diagnosis of autism identified altered energy metabolism in temporal neocortex, caudate, and cerebellum
among ASD cases.23 Other related work in tuberous sclerosis cases with an ASD identified a relationship between clinical presentation and tuber localization.24-26 Most
consistent here is the finding that patients with cerebellar lesions are more severely affected in terms of ASD symptoms compared with patients with lesions restricted to
other brain regions. As with patients with homozygous
mutations in CNTNAP2, white matter heterotopias may
also contribute to ASD features and/or seizures.18
Together, these results suggest that these different
monogenic risk factors for autism share a common involvement of frontal and temporal neocortex, caudate,
and cerebellum. In some cases, these mutations may act
on distinct brain regions to give rise to overlapping neurobehavioral phenotypes, consistent with the notion of
disconnection or circuit disruption.2 The advent of new
imaging paradigms, such as the study of structural connectivity between brain regions by diffusion tensor
imaging or brain networks using functional magnetic resonance imaging, and the extension of these studies to other
rare autism-related syndromes promise to further refine
our knowledge of the core circuits shared by monogenic disorders that result in ASD.
the context of other work showing selective increases in
late-developing white matter in both autism and developmental language disorder,32 suggestive of disrupted connectivity in both conditions.33 Available data support preferential involvement of specific regions, including frontal
and temporal cortex, cerebellum, and amygdala,34 nicely
paralleling both results reviewed earlier and histopathological studies in idiopathic cases summarized later.
As noted elsewhere,27 such regional effects need not
point to differential involvement between brain regions
but may simply reflect asynchronous development between them. Consistent with this notion, it is well established that frontal gray matter and the white matter
tracts projecting to it show protracted growth.35 Likewise, not all regions are bigger in cases compared with
controls. The corpus callosum, the major white matter
tract underlying interhemispheric information transfer,
for example, is smaller by about 10% in cases compared
with controls.36 Separate work showing that frontal and
temporal sulci are abnormally shifted in older affected
children37 together with evidence of prominent frontal
enrichment in the expression of several established ASD
genes (B.S.A. and D.H.G., unpublished data, 2009, and
findings by Abrahams et al20), however, suggest that these
regional findings are most likely the result of differential involvement. These observations also suggest that
other genes with such focal frontal or temporal cortical
localization in early human brain development may represent candidates of particular interest. Similarly, the protracted patterning of the frontal and temporal cortex may
contribute to both the frequency of the ASDs as well as
the observed clinical heterogeneity. Although available
evidence is limited, regions implicated by imaging and
pathological findings generally fit with what is known
about the anatomy of social cognition and language, providing a sense of validation between genetics and brain
circuits.20,38 Evidence for abnormal development in the
second year of life27 together with deficits in structure
and function in adults provide a good entry point into
neuropathological studies, which we will now discuss.
Idiopathic ASD cases—diverse with regard to both etiology and presentation—have been most extensively studied. At the same time, because of this extensive variability, a study of 10 or 20 randomly selected autistic patients
may be best described as individuals with 10 or more different disorders. It is therefore not surprising that relatively little has emerged as consistent in terms of neuropathological findings among idiopathic cases. Not all is
lost, however. The well-replicated finding of accelerated postnatal growth in defined brain regions of cases
compared with controls27 suggests that a major subset
of known and yet to be identified risk factors must contribute to this shared phenotype. Exceptions exist,28 but
similar observations have been made by a number of
groups in both simplex and multiplex cohorts.29-31 Evidence of early accelerated head growth is intriguing in
The most consistent neuropathological finding among the
ASDs is the observation of errors in neuronal migration,39 particularly in frontal and temporal lobes. Like findings from syndromic cases discussed earlier, however,
these results suggest that a diverse number of missteps
can give rise to an ASD. One intriguing observation is
based on the examination of cortical minicolumns: organizations of cells, perpendicular to that pial surface,
thought to contribute to integration of neuronal information across cortical layers. While cortical thickness at
least on average appears similar between cases and controls,40 examination of spacing between minicolumns revealed that relative to typically developing individuals,
distance is reduced in the frontal and temporal cortex of
individuals with a spectrum condition.41
Like the accelerated frontal growth described earlier,
narrow minicolumns in cases may represent a pathologi-
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cal feature able to transcend individual causes. Recent
results indicating similarly narrow columnar spacing
among distinguished scientists42 fit with the notion that
variation here occurs along a continuum that may be related to specific aspects of cognition as opposed to affection status. Because minicolumn findings are predominant in the frontal and temporal cortex, results mesh
well with expression patterns for known ASD genes
CNTNAP220 and MET (Zohar Mukamel, PhD, and D.H.G.,
2009, unpublished data); it is possible that variation in
additional genes yet to be identified that have similar patterns of restricted expression may also be contributory
to specific aspects of brain patterning modulating core
aspects of disease.
The amygdala, involved in the modulation of social
behavior, has long been implicated in the ASDs. Early
work from Bauman and Kemper43 in which histopathological analyses in a control subject were contrasted against
those in an individual with autism and seizures determined that neurons in the amygdala were abnormally
small and showed elevated packing density. Subsequent
work using modern stereological methods in a larger, seizure-free cohort found different, albeit related, abnormalities with fewer neurons in the amygdala of cases compared with controls.44 The fact that the effects were most
prominent in the lateral nucleus of the amygdala is intriguing given that a reduced neuronal number has also
been observed in this structure in schizophrenia.45
Finally, no discussion of ASD histopathological findings would be complete without mention of anomalies
detected in Purkinje cells of the cerebellum.39,43,46 Although recent stereologically based methods found no
significant groupwise differences between cases and controls,47 this work did observe abnormalities in a full half
of all probands. Rather than being dismissed as inconsistent, these results highlight the need to pursue such
investigations with a focus on individual cases in the context of genetic and environmental factors that contribute toward etiology. Averaging across cases likely to have
many different etiologies only serves to obscure observations likely to hold in more homogeneous subgroups.
Good neuropathological analyses on large numbers of
well-phenotyped patients of known head size and the integration of these data with genetic analyses will permit
the determination of how specific risk factors shape developmental brain patterning and subsequently come to
influence behavior.
Understanding how broadly expressed genes give rise to
regionalized deficits in brain anatomy and connectivity
represents a major challenge for the field. Although a variety of hypotheses will need to be explored, one possibility is that such molecules may lead to localized findings via interaction with other, more focally expressed
molecules. Alternatively, subtle but global disruption of
brain circuits may preferentially affect the more vulnerable higher-order association areas that depend heavily
on the precise timing of input from other regions. Asymmetrical brain development and function are also critical, particularly given observed abnormalities in the ASD
brain.48 Further complicating matters is that at least some
of the structures and circuits relevant to known pathophysiology have diverged substantially between humans and rodents. A key hypothesis that integrates these
potential mechanisms and accommodates the evergrowing list of candidate genes1 is that connectivity between frontal, temporal, and additional interconnected
regions mediating language and social behavior is critical to understanding the ASDs.2 Regardless, the union
of genetics and anatomy through concurrent investigation of etiology and pathology within individual cases represents an entry point into disease mechanisms and provides hope for improved patient care.
Accepted for Publication: February 18, 2009.
Correspondence: Daniel H. Geschwind, MD, PhD, Neurogenetics Program, Neurology Department, David Geffen School of Medicine, University of California, Los Angeles, Gonda Bldg 2506, Los Angeles, CA 90095-1769
([email protected]).
Author Contributions: Study concept and design: Abrahams and Geschwind. Analysis and interpretation of data:
Abrahams and Geschwind. Drafting of the manuscript:
Abrahams and Geschwind. Critical revision of the manuscript for important intellectual content: Abrahams and
Geschwind. Obtained funding: Geschwind. Administrative, technical, and material support: Geschwind. Study supervision: Geschwind.
Financial Disclosure: None reported.
Funding/Support: The work in the Geschwind laboratory is supported by Autism Speaks, the Cure Autism Now
Foundation, and grants U54 MH68172, P50 HD055784,
R01 MH64547, and R37 MH60233 from the National Institute of Mental Health.
Additional Contributions: We thank the families who
participate in our genetic studies, especially the Autism
Genetic Resource Exchange (http://www.AGRE.org), and
our many colleagues and collaborators.
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