Clinical Review & Education

JAMA Psychiatry | Review

The Emerging Clinical Neuroscience

of Autism Spectrum Disorder
A Review
Rebecca A. Muhle, MD, PhD; Hannah E. Reed, MD; Katharine A. Stratigos, MD; Jeremy Veenstra-VanderWeele, MD

Related article
IMPORTANCE Autism spectrum disorder (ASD) is a highly prevalent disorder, and community
psychiatrists are likely to treat many individuals with ASD during their clinical practice. This
clinical case challenge describes a routine evaluation of irritability and self-injury in a
preschool-aged child who meets the criteria for ASD. The case also illustrates the importance
of known risk factors for ASD, such as chromosomal deletion and prematurity. This clinical
neuroscience article seeks to educate the clinician of current avenues of research that can
inform and may already affect clinical practice for this patient, while providing a preview of
research that may yield biological treatments for ASD within the next decade.

OBSERVATIONS A diagnosis of ASD is defined behaviorally; therefore, many genetic and

environmental risk factors, working singly or in concert, are linked to ASD. The prenatal
period of brain development is particularly sensitive to risk factors such as gene mutation or
drug exposure that affect brain development and circuitry formation. Currently,
neuroimaging researchers can detect changes in brain connectivity of children with ASD as
young as 6 months, followed by an atypical trajectory of brain development through
preschool age and ongoing connectivity inefficiencies across the lifespan. Animal and cellular
Author Affiliations: Child Study
model systems have provided a means for defining the molecular and cellular changes
Center, Yale School of Medicine, New
associated with risk factors for ASD. The ability to connect specific treatments to particular Haven, Connecticut (Muhle);
subgroups of people with ASD is the defining hope of precision medicine initiatives. Department of Psychiatry, Columbia
University, New York, New York
(Reed, Stratigos,
CONCLUSIONS AND RELEVANCE The advent of next-generation sequencing technology,
Veenstra-VanderWeele); New York
advanced imaging techniques, and cutting-edge molecular techniques for modeling ASD has State Psychiatric Institute, New York
allowed researchers to define ASD risk-related biological pathways and circuits that may, for (Reed, Stratigos,
the first time, unify the effects of disparate risk factors into common neurobiological Veenstra-VanderWeele); Center for
Autism and the Developing Brain,
mechanisms. The path from these mechanisms to biological treatments that improve the NewYork-Presbyterian Hospital, New
lives of individuals with autism remains unclear, but the cumulative output of multiple lines of York, New York (Reed, Veenstra-
research suggests that subtyping by genetic risk factors may be a particularly tractable way to VanderWeele).
capitalize on individual differences amenable to specific treatments. Corresponding Author: Jeremy
Veenstra-VanderWeele, MD,
Department of Psychiatry, Columbia
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.4685 University, 1051 Riverside Dr, Mail
Published online March 28, 2018. Unit 78, New York, NY 10032 (jeremy
.veenstra@nyspi.columbia.edu).

T
he Clinical Challenge in this issue of JAMA Psychiatry
describes a young boy who presented with irritability and
self-injury in the context of developmental delay, social
deficits, and restricted, repetitive behaviors.1 Evaluation confirmed
a diagnosis of autism spectrum disorder (ASD), along with intellectual
and language impairments per DSM-5 criteria (Table 1). 16p11.2 Dele-
tion syndrome can also be added to the diagnosis, to indicate relevant
neurodevelopmental and medical co-occurring conditions. However,
this molecular genetic diagnosis did not change the process of evalu-
ating him in the psychiatric clinic, and there are currently no pharma-
cologic treatment recommendations based on genotype. Research-
ers are just beginning to test treatments for core symptoms based on
biologicalfindingsinsubgroupsofchildrenwithASD,andcurrenttreat-
ments therefore remain either behavioral or applied only to co-
occurringsymptoms.ThiscaseillustrateswhereweareinthearcofASD
assessment and care: at the cusp of incorporating an understanding
of autism neurobiology into treatment, but not quite there yet.
Parallelingrapidadvancesinautismresearch,wehaveseenasurge
in the recognition and diagnosis of ASD, and current prevalence rates
are estimated at 1% to 2%, with 4 to 5 males receiving a diagnosis for
every female who receives a diagnosis of ASD. This surge, coupled with
fraudulent research, led to concerns that vaccines could contribute to
the risk of ASD, which has clearly been disproven.2 Most data instead
point to increased awareness and resources for screening, diminished
stigma, and changes in diagnostic criteria as explanations of today’s
higher recognition of ASD. A few known risk factors, such as advanced
parental age and surviving extreme preterm birth, are also increasing
in parallel with ASD prevalence.

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 Clinical Review & Education Review The Emerging Clinical Neuroscience of Autism Spectrum Disorder

cations for screening. Third, we describe the use of model systems,

Table 1. DSM-5 Criteria for Autism Spectrum Disorder (299.00 [F84.0])
from fish to mice to human cells, to illuminate the neurobiology that
Restricted Interests, Repetitive
Social Communication Domain Behavior Domain
connects genes to behavioral outcomes. Finally, we highlight the
Manifested by all of the following Manifested by at least 2 of the promise of precision medicine that could emerge from an under-
(currently or by history): following (currently or by history): standing of neurobiology.
Deficits in social-emotional Stereotyped or repetitive motor
reciprocity movements, use of objects, or
speech
Deficits in nonverbal communicative Insistence on sameness,
behaviors used for social interaction inflexible adherence to routines, Theme 1: Risk Factors for ASD
or ritualized patterns of verbal
or nonverbal behavior In1943,thefirstdescriptionbyKanner3 ofautisticdisturbancesincluded
Deficits in developing, maintaining, Highly restricted, fixated speculationaboutgeneticinheritance,butearlypsychoanalytichypoth-
and understanding relationships interests that are abnormal in
intensity or focus eses focused on the early social environment as a cause for autism, in-
Hyper- or hyporeactivity to cludingthefallacyofthe“refrigeratormother.”4 Inthe1970s,twinstud-
sensory input or unusual ies identified genetics as a major contributor to the risk of autism.5
interest in sensory aspects of
the environment Within the heterogeneous spectrum of ASD, data point to both genetic
Level 3: requiring very substantial and environmental risk factors that contribute to risk. In the described
support case, the patient has a genetic diagnosis of 16p11.2 microdeletion and
Severe deficits in verbal and Inflexibility of behavior, extreme
nonverbal social communication skills difficulty coping with change, or
a birth history of prematurity, risk factors that both likely contribute to
cause severe impairments in other restricted or repetitive his presentation and diagnosis of ASD.
functioning, very limited initiation of behaviors markedly interfere with
social interactions, and minimal functioning in all spheres; great
response to social overtures from distress or difficulty changing focus Genetic Risk Factors
others or action
Familystudiesindicatethatsharedgeneticriskfactorsincreasethelike-
Level 2: requiring substantial support
lihoodofautism.Identicaltwinshaveautismconcordanceratesof50%
Marked deficits in verbal and Inflexibility of behavior, difficulty
nonverbal social communication coping with change, or other to80%inmoststudies,indicatingstrongheritabilitybutalsothatother
skills, social impairments apparent restricted and repetitive behaviors factors determine whether ASD develops.6-9 Fraternal twins have up
even with supports in place, limited appear frequently enough to be
initiation of social interactions, and obvious to the casual observer and to 30% concordance,6,7,10 whereas the overall rate of recurrence be-
reduced or abnormal responses to interfere with functioning in a tween siblings is approximately 25%.7,8,11 Sibling recurrence increases
social overtures from others variety of contexts; distress and/or
difficulty changing focus or action to 50% if there are 2 or more siblings with ASD or if any affected sib-
Level 1: requiring support ling is female.12,13
Without supports in place, deficits in Inflexibility of behavior causes Common variants (those present in >1% of the population) con-
social communication cause significant interference with tribute the majority of ASD risk at a population level,14,15 but individual
noticeable impairments; difficulty functioning in 1 or more contexts;
initiating social interactions and clear difficulty switching between commonvariantscontributeonlyasmallportionoftheoverallrisk,sug-
examples of atypical or unsuccessful activities; problems of organization gesting that they must act in concert. Genome-wide association is a
responses to social overtures of and planning hamper independence
others; may appear to have decreased powerful method to link common variation in specific genetic regions
interest in social interactions
to the risk of ASD, but these studies require large sample sizes to re-
Symptoms cause clinically significant impairment in social, occupational, or
other important areas of current functioning producibly link risk to specific common variants.16 Additional research
Symptoms must be present in the early developmental period will be needed to understand how multiple common variants interact
These disturbances are not better explained by intellectual disability with each other and with unique environmental exposures to result in
(intellectual developmental disorder) or global developmental delay; to make an outcome of ASD.
comorbid diagnoses of autism spectrum disorder and intellectual disability,
social communication should be below that expected for general Rapidprogresshasbeenmadeinthediscoveryofraregeneticvari-
developmental level ants (present in <1% of the population) that are associated with the risk
Specifiers of ASD (Figure 1). These genetic variants are likely rare owing to det-
Intellectual impairment rimental biological effects that affect the carrier’s reproductive fitness.
Language impairment Rare genetic syndromes (eg, fragile X syndrome and tuberous sclero-
Known genetic, medical, or sis) have long been known to contribute to the risk of ASD17 and can
environmental factor
arise spontaneously (de novo) in the germline. Researchers can now
Associated with another
neurodevelopmental, mental, or compare the genetic information from a child with ASD with the ge-
behavioral disorder netic information from his or her unaffected family members using se-
Catatonia quencing and microarray techniques that survey the entire genome to
identify de novo variants at large scale. De novo variants present only
Here, we focus on a few themes in ASD research that are either in the child with ASD are more likely to contribute to the ASD diagno-
already affecting clinical practice or are likely to affect clinical prac- sis and can be more confidently associated with ASD risk. Research-
tice within the next 5 to 10 years, with an emphasis on research rel- ers first assessed the entire genome for rare de novo microdeletions
evant to 16p11.2 deletion syndrome. First, we discuss the growing and microduplications (copy number variants [CNVs]) using chromo-
understanding of the risk of ASD, both genetic and environmental, somal microarrays. De novo CNVs were detected at a higher frequency
and how identification of risk factors can guide clinical care. Sec- in participants with ASD than in their unaffected siblings, and several
ond, we outline emerging data on neurodevelopmental changes as- recurrent CNVs have been linked to ASD risk,18-22 including 16p11.2
sociated with ASD that support the early onset of ASD, with impli- (Table 220,23-49).

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 The Emerging Clinical Neuroscience of Autism Spectrum Disorder Review Clinical Review & Education

Figure 1. Genetic Risk Variants Associated With the Development of ASD

A Inherited genetic risk variants De novo genetic risk variants

ASD ASD ASD

Common and/or rare variants De novo variant

Genetic variants associated with autism spectrum disorder (ASD) Clinical examples Genetic test

Aneuploidy Trisomy Trisomy 21 Cytogenetics

(karyotyping)
Normal Sex chromosome
aneuploidy Chromosomal
Monosomy (XXY, XXYY) microarray

Copy number variant (CNV) 16p11.2 Deletion Chromosomal

syndrome microarray
Deletion Normal Duplication
16p11.2 Duplication Fluorescence in situ
syndrome hybridization (FISH)

(see Table 2 for

other examples)

Coding Fragile X syndrome PCR fragment

Trinucleotide repeat expansion Untranslated region region Intron
FMR1 gene length analysis
Normal <50 CGG repeats Fragile XE syndrome

Premutation carrier 50-200 CGG repeats

Affected >200 methylated CGG repeats

Nucleotide insertion and/or deletion (indel) Single-nucleotide variant (SNV) ASD associated with Whole exome
CHD8 mutation sequencing
Normal Normal
ASD with Targeted gene
DNA DNA macrocephaly sequencing by PCR
associated with
Protein Protein
PTEN mutation

Insertion Indel Substitution SNV (see Table 3 for

other examples)
DNA DNA

Protein STOP Protein STOP

Premature stop codon Premature stop codon

A, Pedigrees of people affected with autism spectrum disorder (ASD) and their families. Left, pedigree of a family demonstrating multiple inherited genetic risk factors in
the affected children of 2 nonaffected parents. Right, pedigree of a family showing the development of a new mutation in the offspring that contributed to the develop-
ment of ASD in that child. B, Large- and small-scale genetic changes associated with increased risk of ASD. The different classes of genetic variants are presented by size,
from large-scale alterations (entire chromosomes or large regions missing or duplicated) at the top, to substitutions of just 1 DNA nucleotide at the bottom. Examples of
DNA sequence changes in the coding region of the CHD8 gene associated with ASD are presented in the bottom panel. Sequence corresponds to chromosome 14 (hg19),
21 878 138 to 21 878 130 base pairs (left) and 21 870 179 to 21 870 160 base pairs (right). Variants may be inherited from a carrier parent or develop de novo in the person
with ASD. Variants that are more damaging to biological function are less likely to be inherited and may interact with other genetic, environmental, and developmental risk
factors to yield a clinical diagnosis of ASD. Single-nucleotide polymorphisms (SNPs) (not depicted) are common variants that contribute to ASD risk, but at this time, indi-
vidual SNPs have not been linked to risk for ASD to justify clinical screening. Whole-genome sequencing detects copy number and nucleotide sequence variants, but it is not
yet clinically available for molecular genetic diagnostic testing owing to increased expense and data storage limitations. PCR indicates polymerase chain reaction.

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 Clinical Review & Education Review The Emerging Clinical Neuroscience of Autism Spectrum Disorder

Table 2. Recurrent De Novo Copy Number Variants (CNVs) Associated With Autism Spectrum Disordera

CNV Locus Copy Number Change Other Associated Conditions Syndrome Name
1q21.1 Duplication ID, SCZ, ADHD, seizures, macrocephaly, CHD, scoliosis, and short 1q21.1 Duplication syndrome
stature23,24
2p16.3 Deletion ID, speech delay, SCZ, seizures, macrocephaly, dysmorphology, CHD, and 2p16.3 Deletion syndrome
hypotonia25-27
3q29 Deletion ID, speech delay, SCZ, anxiety disorder, dysmorphology, dental 3q29 Microdeletion syndrome
abnormalities, FTT, gastrointestinal problems, CHD, and recurrent ear
infections28,29
7q11.23 Duplication ID, speech delay, ADHD, anxiety disorder, seizures, macrocephaly, Williams-Beuren syndrome
dysmorphology, CHD, and renal anomalies30-32
15q11.2-q13.1 Duplication ID, ADHD, seizures, hypotonia, CHD, and short stature33-38 15q11.2-q13.1 Duplication syndrome
15q13.2-q13.3 Deletion ID and ADHD33,39 15q13.3 Microdeletion syndrome
15q13.2-q13.3 Duplication ID, speech delay, epilepsy, urogenital anomalies, and recurrent 15q11-q13 Duplication syndrome
infections33,36
16p11.2 Deletion ID, ADHD, DCD, seizures, macrocephaly, obesity, hypotonia, and 16p11.2 Deletion syndrome
articulation abnormalities40-42
16p11.2 Duplication ID, SCZ, seizures, microcephaly, hypotonia, tremor, and articulation 16p11.2 Duplication syndrome
abnormalities40,41,43
22q11.2 Deletion ID, learning disorder, speech delay, SCZ, ADHD, anxiety disorder, Velocardiofacial syndrome, DiGeorge
dysmorphology, palate abnormalities, CHD, renal anomalies, hypocalcemia, syndrome
and recurrent infections44
22q11.2 Duplication ID, ADHD, learning disorder, hypotonia, hearing loss, palate abnormalities, 22q11.2 Microduplication syndrome
CHD, urogenital anomalies, and growth retardation45-47
22q13.3 Deletion ID, seizures, macrocephaly, dysmorphology, strabismus, CHD, renal Phelan-McDermid syndrome
anomalies, hypotonia, and scoliosis48,49
a
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CHD, congenital Copy number variants associated with autism spectrum disorder sourced from
heart disease; DCD, developmental coordination disorder; FTT, failure to thrive; Sanders et al.20
ID, intellectual disability; SCZ, schizophrenia.

More recently, geneticists have examined the protein-coding re-
gions of the genome (the exome) using whole-exome sequencing,
which allows detection of single-nucleotide variants. Compared with
their unaffected siblings, children with ASD had an elevated rate of
rare, de novo, single-nucleotide variants and insertions and/or de-
letions that likely disrupt genes (Figure 1).20,50-53 Combined analy-
sis of multiple family cohorts found that individual genes could be
confidently assigned ASD risk based on being disrupted in affected
individuals more frequently than could be expected by chance
(Table 3).20 These genes cluster into the following 2 groups: 1 en-
riched for proteins involved in brain function (eg, synaptic function-
ing and neuron projection) and the other enriched for gene regula-
tion (eg, chromatin organization and transcription). Using
computational approaches incorporating a gene expression atlas of
the human brain across the lifespan, researchers identified en-
riched coexpression of ASD risk genes in specific cortical regions from
early gestation to midgestation.54,55
As remarkable as progress has been, the known variants are just
the tip of the iceberg. Modeling predicts that approximately 200 de
novo CNVs and hundreds of genes contribute to ASD risk,20,53 likely
interacting with environmental risk factors to result in ASD. Al-
though each of these variants may be individually rare, collectively
they are found in a large minority of the clinical population with ASD.
Currently, medical associations recommend molecular diagnostic
testing using chromosomal microarray and fragile X testing in all
people diagnosed as having ASD, and adjunctive clinical whole-
exome sequencing may be helpful in those with congenital abnor-
malities or unexplained co-occurring medical conditions.56,57 The
identification of a molecular diagnosis can provide clinical care guide-
lines and may warn of potential comorbidities that would other-
wise go unmonitored.
The patient carried a microdeletion of 16p11.2, a region that en-
compasses 29 genes. There are now several large clinical cohorts with
16p11.2 deletions (del16p11.2) and duplications (dup16p11.2), and as-
sociations have been reported with ASD, schizophrenia, intellec-
tual disability, and seizures.20,58-60 People carrying 16p11.2 CNVs ex-
hibit mirror phenotypes: deletion is associated with obesity and
macrocephaly,60-63 while duplication is associated with lower weight
and microcephaly.19,59,64 Some people with a 16p11.2 CNV do not
have a clinical disorder, but performance IQ and general function-
ing may be lower compared with the general population.65,66 There
are likely additional genetic and environmental modifiers that ulti-
mately dictate whether the carrier has a particular disorder and to
what degree.67
Environmental Risk Factors
As noted previously, twin studies suggest that both genetic and en-
vironmental risk factors are associated with ASD (Figure 2). Poten-
tial nongenetic risk factors include maternal conditions, complica-
tions of pregnancy, medications, and exposure to toxic materials.
Most of these risk factors act on brain development during the pre-
natal and perinatal stages. Establishing causal roles for environmen-
tal factors is complicated by retrospective reporting and overlap-
ping risk factors, but several nongenetic risk factors for ASD have
now been established.
The most well-supported environmental risk factor for ASD is
advanced parental age,68-71 with most evidence suggesting that this
contributes to genetic risk. Maternal and paternal age appear to be
independent risk factors, leading to an 18% (for mothers) and 21%
(for fathers) increase in ASD risk for every 10-year increase in the age
of the parent.71 The risk of chromosomal abnormalities is well known
in mothers of advanced maternal age, and prenatal genetic screen-

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 The Emerging Clinical Neuroscience of Autism Spectrum Disorder Review Clinical Review & Education

Table 3. High-Confidence Autism Spectrum Disorder Risk Genesa

Gene OMIM Cytogenetic Molecular Function or
Symbol Identifier Location Biological Processb Associated Syndromesc
ADNP 611386 20q13.13 Transcription Helsmoortel-van der Aa syndrome
ANK2 106410 4q25-q26 Protein transport Cardiac arrhythmia, ankyrin-B–related
ARID1B 614556 6q25.3 Transcription Coffin Siris syndrome 1
ASH1L 607999 1q22 Transcription Autosomal dominant mental retardation 52
ASXL3 615115 18q12.1 Transcription Bainbridge-Ropers syndrome
a
CHD8 610528 14q11.2 Transcription Autism, susceptibility to, 18 Genes harboring multiple, rare,
CUL3 603136 2q36.2 Transport Pseudohypoaldosteronism, type IIE single-gene mutations that are
scored as 1 (high confidence) by a
DSCAM 602523 21q22.2 Cell adhesion None Simons Foundation Autism
DYRK1A 600855 21q22.13 Protein kinase Mental retardation, autosomal dominant 7 Research Initiative gene scoring
GRIN2B 138252 12p13.1 Ion transport Early infantile epileptic encephalopathy 27 advisory panel (https://gene.sfari
.org). This is an iteratively curated
KATNAL2 614697 18q21.1 Hydrolase None list of >800 human genes with
KMT2A 159555 11q23.3 Transcription Wiedemann-Steiner syndrome genetic, clinical, or functional
KMT5B 610881 11q13.2 Transcription Mental retardation, autosomal dominant 51 evidence of association with risk of
autism spectrum disorder, with
MYT1L 613084 2p25.3 Transcription Mental retardation, autosomal dominant 39 highest ranking reserved for genes
NAA15 608000 4q31.1 Transcription Mental retardation, autosomal dominant 50 with independently verified,
POGZ 614787 1q21.3 Cell cycle White-Sutton syndrome genome-wide statistical significance
between cases and controls.
PTEN 601728 10q23.31 Apoptosis Cowden syndrome I, macrocephaly/autism syndrome b
Molecular function or biological
RELN 600514 7q22.1 Cell adhesion Lissencephaly 2 (Norman-Roberts type) process keywords were retrieved
SCN2A 182390 2q24.3 Ion transport Epileptic encephalopathy, early infantile, 11 for each gene from Uniprot (http:
//www.uniprot.org).
SETD5 615743 3p25.3 Transcription Mental retardation, autosomal dominant 23
c
Associated syndromes were
SHANK3 606230 22q13.33 Axon guidance Phelan-McDermid syndrome
retrieved for each gene from OMIM
SYNGAP1 603384 6p21.32 Dendrite development Mental retardation, autosomal dominant 5 (http://omim.org). Mental
TBR1 604616 2q24.2 Transcription None retardation is a retired term that is
now currently described as
TRIP12 604506 2q36.3 DNA repair Mental retardation, autosomal dominant 49
intellectual disability.

ing is routinely offered in this population. Older fathers contribute
more de novo mutations as they age.50,52,72 The total elevated risk
is likely owing to other factors as well, including an increase in com-
plications of pregnancy, epigenetic modifications of the genome, and
social factors that may contribute to having children later in life.71
Prematurity, even up to 37 weeks, is another well-established
risk factor for ASD.70,73 The preterm brain has vulnerability to cer-
tain forms of gray and white matter brain injury that affect subcor-
tical and cortical connectivity (theme 2); however, preterm birth is
associated with ASD even in the absence of overt neuronal injury.74
The elevated risk of ASD is likely compounded by prematurity-
associated complications, such as anoxia and hypoglycemia. The risk
for ASD is greatest in extremely preterm infants. In those with very
low birth weight and extreme preterm birth, ASD is more likely to
be associated with major cognitive and motor impairments.75 In the
case presented, the patient was born at a gestational age of 32 weeks,
a time when the brain is still in the migration phase and has begun
synaptic pruning and myelination (Figure 2). This child therefore ap-
pears to have 2 independent risk factors for ASD.
Dozens of other environmental factors have been linked with
ASD, although further evidence is needed to consider them as es-
tablished risk factors for ASD. These risk factors can generally be cat-
egorized as either endogenous, originating from within the maternal-
fetal unit, or exogenous, originating from outside of the mother.76
The endogenous risk factors with the best support, outside of pre-
maturity, are short-interval pregnancies, defined as pregnancies oc-
curring fewer than 12 months apart70; birth complications involv-
ing hypoxia and ischemia or trauma; maternal obesity; and diabetes.71
Exogenous risk factors, such as medication exposure during preg-
nancy, also play a role in the risk of ASD. The prenatal use of anti-
convulsants has been associated with an increased risk of ASD, with
valproic acid use during pregnancy showing the clearest
association.70,77 Asthma medications, particularly β2-adrenergic re-
ceptor agonists, have also been linked to autism risk.70 Although still
controversial, there is emerging evidence to support prenatal ex-
posure to air pollution as a risk factor for ASD.70,71
Environmental risk factors for ASD have significant implica-
tions for public policy and prenatal health care. Discerning the mecha-
nisms behind environmental risks may be particularly difficult, how-
ever, because they may act directly on neurons and supporting cells
or may act indirectly by influencing hormones or inflammatory re-
sponses. Alternatively, environmental risks may act by altering the
expression of relevant genes that affect ASD risk. Despite the diver-
sity of genetic and environmental risk factors in ASD, it is important
to understand how they may interact and lead to downstream ef-
fects on brain development, and thereby indicate common path-
ways underlying the core deficits of ASD.
Theme 2: Altered Brain Development in ASD
Neuroimaging studies increasingly support a picture of early atypi-
cal brain development and widespread alterations in neural con-
nectivity in individuals with ASD. Some of the most promising find-
ings are in infants and toddlers who have an older sibling with ASD,
and are therefore at increased risk for ASD. Prospective neuroim-

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 Clinical Review & Education Review The Emerging Clinical Neuroscience of Autism Spectrum Disorder

Figure 2. Risk Factors in ASD and Timeline of Brain Development

A Risk factors associated with autism spectrum disorder (ASD)

Advanced parental age Maternal obesity and diabetes Premature birth

Short-interval pregnancy Prenatal exposure to certain medications Birth complications
(<12 months apart) (anticonvulsants; β2-adrenergic receptor agonists) (hypoxia; trauma)
Mutations in ASD risk genes (see Figure 1)

B Timeline of brain development and alterations in ASD

Prenatal Postnatal
Normal brain development A, The majority of known risk factors
Neurulation for autism spectrum disorder (ASD)
Neural proliferation occur primarily before conception or
during prenatal development. B, The
Neural apoptosis
earliest published data on brain
Neural migration
development in ASD are at 6 months
Synaptogenesis of age. These data indicate that, by at
Synaptic pruning least that time point, both brain
Myelination volume and connectivity are affected.
It is presumed that these changes
Peak expression of ASD risk genes begin earlier in development,
Genes involved in chromatin organization although the exact timing and
and transcription regulation mechanisms are unknown. Changes
Genes involved in synaptic function in brain development in ASD likely
and neuronal projection begin during the prenatal period,
when many ASD risk genes have peak
Alterations in brain development in ASD
expression levels. It is further
Abnormal neural apoptosis (hypothesized) ? hypothesized that brain development
Abnormal synaptic pruning ? in ASD may involve abnormal
(hypothesized) synaptic pruning and/or neural
Brain volume enlargement
apoptosis during this time. If
Atypical brain connectivity appropriate pruning and/or apoptosis
fail to occur early in development,
First trimester Second trimester Third trimester Year 1 Year 2 Year 3 Year 4 Year 5 this may manifest later as atypical
Birth Early behavioral Median age at connectivity and brain volume
changes ASD diagnosis enlargement, particularly once
myelination begins.

aging studies consistently point to abnormal trajectories of brain de-
velopment, rather than static changes or localized lesions. Effec-
tive brain development depends on the balance between cellular and
synaptic growth and appropriately timed pruning of neurons and syn-
apses. In at least some children with ASD, this balance appears to
be disrupted.
Neuroimaging studies find that changes occur well before the
onset of clear symptoms of ASD. The association of risk with pre-
natal exposures suggests that many of these disruptions begin dur-
ing the prenatal period. Recent neuroimaging studies have exam-
ined brain development in high-risk infants from 6 months of age,
suggesting that infants who will later develop ASD already exhibit
abnormal connectivity by this time.78-81 Connections involved in low-
level sensory processing appear particularly affected at this early
stage.81 In some studies, the degree of atypical connectivity at 6
months correlates with future symptom severity.79,81
Starting between the ages of 6 and 12 months, children who will
go on to have ASD show an expansion of cortical surface area, starting
insensorydomainsunderlyingauditoryandvisualprocessing,followed
by more global overgrowth from the ages of 12 to 24 months.82,83 This
trajectory mirrors typical development, but in an exaggerated manner
(Figure 2). In typical development, brain growth during this period is
largely attributed to the expansion of glia and myelination.84 Similarly,
in individuals with ASD, this observed overgrowth likely does not rep-
resent new neuron development, although it could reflect overgrowth
owing to a surplus of neurons that did not undergo typical apoptosis
and pruning earlier in development.
From the ages of 2 to 4 years, brain volumes in children with ASD
remain enlarged compared with those of their peers.85,86 The amyg-
dala, frontal cortex, and temporal cortex, which are important for
social cognition, language, and regulation of emotions, are particu-
larly affected.79,85 By school age, brain growth has slowed, with brain
volumes of typically developing children catching up to those in chil-
dren with ASD.85,86 Connectivity studies find ongoing disruptions
in how brain regions communicate throughout school age, adoles-
cence, and adulthood. A large pooled analysis of resting-state data
from functional magnetic resonance imaging performed in individu-
als with ASD found a predominance of hypoconnectivity of long-
range cortical-cortical and interhemispheric projections compared
with age-matched typical controls.87 In contrast, subcortical re-
gions exhibited hyperconnectivity of local connections. As a whole,
these data suggest that higher-order brain functions requiring com-
munication between separate brain regions are depressed in favor
of local circuits that may be overactive and difficult to disrupt.
The 16p11.2 microdeletion illustrates the strong influence that
genetic variants can have on brain development. Individuals with
a deletion (1 copy of this region) show significantly larger brain
volumes than do unaffected individuals who carry 2 copies.88
Similar to results from general studies of ASD, both gray matter
and white matter are affected by 16p11.2 deletion, particularly in

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 The Emerging Clinical Neuroscience of Autism Spectrum Disorder
regions implicated in reward, language, and social cognition.89
More important, these associations are seen at a group level, with
considerable variability across individuals. Individuals with a
duplication (3 copies) of 16p11.2 tend to have microcephaly, which
is also associated with other ASD risk factors (eg, fetal alcohol
syndrome and DYRK1A [OMIM 600855] disruption) (Table 3).
This dichotomy demonstrates the heterogeneity underlying ASD.
Although neuroimaging research is advancing our under-
standing of the biology of ASD, there is no evidence to support
routine neuroimaging in autistic individuals.90,91 In 16p11.2 dele-
tion syndrome, the recommendation is the same, with the caveat
that individuals with symptoms suggestive of Chiari I malforma-
tion or syringomyelia, conditions that are more common in this
syndrome, should undergo neuroimaging.92 More research is
needed to better understand and standardize the trajectory of
brain development in ASD before neuroimaging could be consid-
ered for a clinical role. These findings do emphasize the utility of
early diagnostic screening, however, and early behavioral inter-
vention is critical to improve social and communication function-
ing. Fine-tuned behavioral screening, such as the use of eye track-
ing to monitor attention to social scenes, could eventually be
used to identify children at risk of ASD before overt symptoms
emerge, but this finding has not yet been demonstrated in clinical
settings.93
Theme 3: Model Systems of ASD
Computational, cellular, and animal model systems can help to
dissect the molecules, cells, and circuits that connect risk factors
for ASD to biology. Model systems are particularly important for
understanding how and when these risk factors affect brain
development and lead to downstream changes in behavior. Ani-
mal models provide a developmentally informed context in which
to study the consequences of a genetic variant on brain struc-
tures and cell types. Even relatively simple animals, such as
zebrafish, have substantial conservation of ASD risk genes. For
example, of the 29 genes in the 16p11.2 CNV in humans, 24 genes
are conserved in zebrafish.94 Rodent and primate models have
more biological similarity to humans and may exhibit behaviors
that may be more analogous to human social or repetitive behav-
ior. Researchers recently created several monkeys with disruption
of the Rett syndrome gene, MECP2 [OMIM 300005], which
exhibited decreased social contact and more stereotyped
behaviors.95 Although primate models are closest in behavior and
biology to humans, ethical issues and their high cost have limited
their widespread use.
The mouse brain is less complex than the human brain, but
mouse models that recapitulate a human gene variant can be cost-
efficient and time-saving while still providing a developmental con-
text to observe the effect of risk factors on specific cells, tissues, and
organs. For example, several altered cellular mechanisms and path-
ways have been identified in mice with the 16p11.2 deletion, includ-
ing premature exiting of neuronal progenitor cells from the cell cycle
and increased dopamine receptor expression on striatal γ-amino-
butyric acid–ergic neurons.96,97 While it must be stated that behav-
ioral tests in mice may not accurately reflect symptom domains of
ASD (or human social cognition more generally), these animals did
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Review Clinical Review & Education
exhibit hyperactivity, repetitive behaviors, and learning deficits remi-
niscent of the human phenotype.96-100
Animal models are also crucial in the development of poten-
tial treatments. For example, mice with del16p11.2 showed dimin-
ished long-term potentiation, similar to a mouse model of fragile
X syndrome.98,101 These animals were unable to acquire or extin-
guish a memory of an unpleasant stimulus, which could be res-
cued by treatment with a glutamate receptor mGluR5 modulator.
More recently, researchers used R-baclofen, a γ-aminobutyric
acid–B receptor agonist, to rescue deficits in object or spatial rec-
ognition in mice with del16p11.2.102
In addition to animal models, new techniques using human
cell lines can illuminate the molecular consequences of genetic
risk variants. For example, using lymphocyte cell lines obtained
from carriers of 16p11.2 CNVs, researchers found that expression
of genes within this region rose or fell with duplications or dele-
tions, as expected, but some genes outside of the region were
also affected, potentially pointing to critical pathways that medi-
ate the risk of ASD.103,104 Alternatively, reprogramming cells into
induced pluripotent stem cells and differentiating them into indi-
vidual neuronal lineages may provide better consistency with
brain cells.105 These cultures have thus far been limited to early
stages of brain development and manifest fewer specific cell
types, but if deficits are identified in cells derived from patients,
therapeutic interventions could be evaluated and provide test-
able targets and hypotheses for clinical research trials.106
Future Directions and the Promise
of Precision Medicine
Based on available evidence, a diagnosis of ASD should be followed as
soon as possible by implementation of early, intensive behavioral in-
tervention,whichimprovescognitiveandadaptiveoutcomesformany
(but not all) preschoolers with ASD.107 Behavioral and educational in-
terventions for school-age children are tailored to individual needs but
have much less research support.107 Evidence-based pharmacologic
treatments in ASD are limited to co-occurring symptoms, such as agi-
tationorhyperactivity.108 Somecliniciansandparentsalsochoosefrom
apanoplyoftreatmentswithnoevidence,drivenbyadesiretoaddress
the root causes of ASD.109 This use of treatments with no evidence is
understandable when none of our available biological treatments are
treating the core neurobiological determinants of the disorder.
Thediscoveryofraresingle-genevariantsandCNVsraisesthepos-
sibility of ASD treatments rooted in biology, rather than in behavioral
principlesorpharmacologicobservations.Thepresenceofaknownge-
netic risk variant in the described child is quite likely to have tipped the
scales toward an ASD outcome. This motivates investigations for treat-
ments targeted to molecular genetic diagnoses rather than to an ASD
diagnosis per se. With the advance of designer gene editing technol-
ogy, it is possible that interventions could be targeted to specific ge-
netic loci (to repair a genetic sequence or to correct aberrant gene
activity),110 althoughthepossibilityofunintendedgeneticchanges(off-
target effects) is currently too large to suggest such interventions for
all but the most devastating syndromes.111
Precision medicines in ASD-related genomic disorders will not
be as straightforward to test as in cancer, in which clinical response
(Reprinted) JAMA Psychiatry Published online March 28, 2018 E7
 Clinical Review & Education Review The Emerging Clinical Neuroscience of Autism Spectrum Disorder

can be measured by tumor regression or normalization of cell counts.
Tests of neurobiological hypotheses in developmental disorders re-
quire careful consideration of our standard protocols. We almost cer-
tainly need to study treatments at an earlier point in childhood de-
velopment, rather than binding ourselves to the standard timeline
of efficacy studies in adults, then in adolescents, and finally in
children.112 We also need to define and refine outcome measures that
are more sensitive to change and that are informed by the experi-
ences and voices of the autistic community.113
The DSM-5 defines ASD by behavioral symptoms and man-
dates the diagnosis of separate disorders to indicate language im-
pairment or inattention. Unlike the DSM-5 approach, with well-
defined splitting between categories, we do not imagine that
independent biological pathways separately lead to ASD symp-
toms, language impairment, and inattention. Instead, it is likely that
neurodevelopmental consequences cascade from risk factors to mul-
tiple domains of difficulty, depending on the genetic or environ-
mental insult and when it is incurred. Here, we have largely de-
scribed ASD as a disorder, but ASD is instead made up of many
different disorders that have core ASD symptoms in common but
many disparate symptoms as well.
Simultaneously,whilewethinkthatallpsychiatristsneedtobepre-
pared for a future in which biological insights lead to transformative
treatments, we must acknowledge that we do not yet live in that fu-
ture. Our neuroscience themes are focused on future clinical effect,
rather than what makes a difference for treatment right now. For the
boy and his family described in the Clinical Challenge,1 knowing his ge-
nomic risk variant allows for family planning, provides insight into one
cause of his disorder, and connects the family to a network of others
withthesamegenomicfinding.Theidentificationofawell-definedbio-
logical risk factor can relieve parental self-blame and reduce the pres-
sure to pursue alternative treatments based on false promises to ad-
dress the causes of ASD. This scenario represents benefit to the patient
and his family right now, even while we wait for the development and
implementation of precision medicines.
Conclusions
Autism spectrum disorder is not a singular disorder, but rather de-
scribes a common set of behavioral features that unite a very hetero-
geneous population reflecting diverse genetic and environmental
risk factors. Genetic testing, including a chromosomal microarray and
fragile X testing, is recommended for all individuals with ASD. While
we await precision medicine treatments based on neurobiology, cli-
nicians should use behavioral approaches for core symptoms and
consider medications only for co-occurring symptoms in addition to
an ongoing behavioral program.

ARTICLE INFORMATION 3. Kanner L. Autistic disturbances of affective stoppage from large UK ASD research family
Accepted for Publication: December 21, 2017. contact. Nerv Child. 1943;2:217-250. databases. Autism Res. 2015;8(1):73-81.

Published Online: March 28, 2018.
doi:10.1001/jamapsychiatry.2017.4685
Author Contributions: Drs Muhle and Reed were
co-first authors and contributed equally to this
work. Drs Muhle and Reed had full access to all the
data in the study and takes responsibility for the
integrity of the data and the accuracy of the data
analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data:
Muhle, Reed.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: Muhle, Reed, Veenstra-
VanderWeele.
Administrative, technical, or material support:
Muhle, Reed.
Study supervision: Veenstra-VanderWeele.
Conflict of Interest Disclosures: Dr Veenstra-
VanderWeele reported serving on advisory boards
or as a consultant for Roche, Novartis, and
SynapDx; receiving research funding from Roche,
Novartis, Seaside Therapeutics, and Forest; and
receiving editorial stipends from Springer and
Wiley. No other conflicts were reported.
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