CHAPTER 19 Autism Spectrum Disorder Scott M. Myers, MD, FAAP In 1943 Leo Kanner eloquently described 11 children with innate “autistic disturbances of affective contact” characterized by profound lack of reciprocal social engagement and interaction; disturbances in communication ranging from mutism to echolalia, pronoun reversal, and literalness; and unusual responses to the environment, including insistence on sameness that was not explained by general cognitive impairment.1 More than 7 decades later, diagnostic criteria and assessment instruments remain remarkably influenced by Kanner’s original description. Definition and Classification: DSM-5 In the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), published in 2013, the DSM-IV umbrella term pervasive developmental disorders and diagnostic classifications autistic disorder, Asperger’s disorder, childhood disintegrative disorder, Rett’s disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS) were replaced by a single diagnostic term, autism spectrum disorder (ASD).2 These changes were prompted by research demonstrating that the subclassifications had little scientific justification and were not used reliably, even by experts.3 The International Classification of Diseases (ICD) criteria, the 11th revision of which are scheduled to be published in 2018, are expected to also include these changes and to be very similar to the DSM-5 criteria.4 The DSM-5 diagnostic criteria for ASD are presented in Box 19.1, and the severity level classification, which is new to the DSM, is described in Box 19.2.2 ASD diagnosis requires meeting all 3 of the social communication and interaction criteria and at least 2 of 4 restricted and repetitive behavior criteria. The symptoms must cause clinically significant impairment in current functioning and must have been present in the early developmental period, although they may not become fully manifest until social demands exceed limited capacities, or they may be masked by learned strategies in later life. To make a diagnosis of ASD in an individual with intellectual disability (ID), social communication and interaction skills must be below what would be expected based on general developmental level. A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text): 1. Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions. 2. Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication. 3. Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers. Specify current severity: Severity is based on social communication impairments and restricted, repetitive patterns of behavior (see Box 19.2). B. Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive; see text): 1. Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies, lining up toys or flipping objects, echolalia, idiosyncratic phrases). 2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns of verbal or nonverbal behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat food every day). 3. Highly restricted, fixated interests that are abnormal in intensity or focus (e.g, strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interest). 4. Hyper- or hypo-reactivity to sensory input or unusual interests in sensory aspects of the environment (e.g., apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement). Specify current severity : Severity is based on social communication impairments and restricted, repetitive patterns of behavior (see Box 19.2). C. Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life). D. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning. E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level. Note: Individuals with a well-established DSM-IV diagnosis of autistic disorder, Asperger’s disorder, or pervasive developmental disorder not otherwise specified should be given the diagnosis of autism spectrum disorder. Individuals who have marked deficits in social communication, but whose symptoms do not otherwise meet criteria for autism spectrum disorder, should be evaluated for social (pragmatic) communication disorder. Specify if: With or without accompanying intellectual impairment With or without accompanying language impairment Associated with a known medical or genetic condition or environmental factor Associated with another neurodevelopmental, mental, or behavioral disorder With catatonia (refer to the criteria for catatonia associated with another mental disorder for definition) a Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright © 2013). American Psychiatric Association. All Rights Reserved. Box 19.2. DSM-5 Severity Levels for Autism Spectrum Disordera
Thomas D. Challman, MD, FAAP
Autism Spectrum Disorder
Scott M. Myers, MD, FAAP
In 1943 Leo Kanner eloquently described 11 children with innate “autistic disturbances of affective contact” characterized by profound lack of reciprocal social engagement and interaction; disturbances in communication ranging from mutism to echolalia, pronoun reversal, and literalness; and unusual responses to the environment, including insistence on sameness that was not explained by general cognitive impairment.1 More than 7 decades later, diagnostic criteria and assessment instruments remain remarkably influenced by Kanner’s original description.
Definition and Classification: DSM-5
In the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), published in 2013, the DSM-IV umbrella term pervasive developmental disorders and diagnostic classifications autistic disorder, Asperger’s disorder, childhood disintegrative disorder, Rett’s disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS) were replaced by a single diagnostic term, autism spectrum disorder (ASD).2 These changes were prompted by research demonstrating that the subclassifications had little scientific justification and were not used reliably, even by experts.3 The International Classification of Diseases (ICD) criteria, the 11th revision of which are scheduled to be published in 2018, are expected to also include these changes and to be very similar to the DSM-5 criteria.4
The DSM-5 diagnostic criteria for ASD are presented in Box 19.1, and the severity level classification, which is new to the DSM, is described in Box 19.2.2 ASD diagnosis requires meeting all 3 of the social communication and interaction criteria and at least 2 of 4 restricted and repetitive behavior criteria. The symptoms must cause clinically significant impairment in current functioning and must have been present in the early developmental period, although they may not become fully manifest until social demands exceed limited capacities, or they may be masked by learned strategies in later life. To make a diagnosis of ASD in an individual with intellectual disability (ID), social communication and interaction skills must be below what would be expected based on general developmental level.
A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text):
1. Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions.
2. Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication.
3. Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers.
Specify current severity: Severity is based on social communication impairments and restricted, repetitive patterns of behavior (see Box 19.2).
B. Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive; see text):
1. Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies, lining up toys or flipping objects, echolalia, idiosyncratic phrases).
2. Insistence on sameness, inflexible adherence to routines, or ritualized patterns of verbal or nonverbal behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat food every day).
3. Highly restricted, fixated interests that are abnormal in intensity or focus (e.g, strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interest).
4. Hyper- or hypo-reactivity to sensory input or unusual interests in sensory aspects of the environment (e.g., apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement).
Specify current severity : Severity is based on social communication impairments and restricted, repetitive patterns of behavior (see Box 19.2).
C. Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life).
D. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.
E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level.
Note: Individuals with a well-established DSM-IV diagnosis of autistic disorder, Asperger’s disorder, or pervasive developmental disorder not otherwise specified should be given the diagnosis of autism spectrum disorder. Individuals who have marked deficits in social communication, but whose symptoms do not otherwise meet criteria for autism spectrum disorder, should be evaluated for social (pragmatic) communication disorder.
With or without accompanying intellectual impairment
With or without accompanying language impairment
Associated with a known medical or genetic condition or environmental factor
Associated with another neurodevelopmental, mental, or behavioral disorder
With catatonia (refer to the criteria for catatonia associated with another mental disorder for definition)
a Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright © 2013). American Psychiatric Association. All Rights Reserved.
Box 19.2. DSM-5 Severity Levels for Autism Spectrum Disordera
Restricted, Repetitive Behaviors
“Requiring very substantial support”
Severe deficits in verbal and nonverbal social communication skills cause severe impairments in functioning, very limited initiation of social interactions, and minimal response to social overtures from others. For example, a person with few words of intelligible speech who rarely initiates interaction and, when he or she does, makes unusual approaches to meet needs only and responds to only very direct social approaches
Inflexibility of behavior, | extreme difficulty coping with change, or other restricted/repetitive behaviors markedly interfere 1 with functioning in all spheres. Great distress/ difficulty changing focus or action.
Marked deficits in verbal and nonverbal social communication skills; social impairments apparent even with supports in place; limited initiation of social interactions; and reduced or abnormal responses to social overtures from others. For example, a person who speaks simple sentences, whose interaction is limited to narrow special interests, and how has markedly odd nonverbal communication.
Inflexibility of behavior, difficulty coping with | change, or other restricted/ repetitive behaviors appear frequently enough to be | obvious to the casual 1 observer and interfere with functioning in a variety of contexts. Distress and/or difficulty changing focus 1 or action.
Without supports in place, deficits in social communication cause noticeable impairments. Difficulty initiating social interactions, and clear examples of atypical or unsuccessful response to social overtures of others. May appear to have decreased interest in social interactions. For example, a person who is able to speak in full sentences and engages in communication but whose to-and-fro conversation with others fails, and whose attempts to make friends are odd and typically unsuccessful.
Inflexibility of behavior causes significant interfer- | ence with functioning in one or more contexts. Difficulty switching between activities. Problems of organization I and planning hamper independence.
Social (pragmatic) communication disorder (SCD) was introduced as a diagnostic classification in DSM-5.2,4 The goal was to more accurately recognize individuals who have early-onset, persistent difficulty using verbal and nonverbal communication for social purposes, leading to significant functional limitations in effective communication, social participation, development and maintenance of social relationships, academic achievement, and/or occupational performance.2 The diagnostic criteria for SCD are provided in Box 19.3.2 By definition, the communication deficits in SCD are not explained by low general cognitive ability or low abilities in the domains of word structure and grammar, and they occur in the absence of the repetitive and restricted behaviors and interests that characterize ASD; in fact, ASD must be ruled out for SCD to be diagnosed. Diagnosis of SCD with other communication disorders is permitted. However, it is expected that diagnosis of SCD would seldom be made before the age of 4 to 5 years, when structural language abilities are often adequate to determine that deficits in pragmatic language are discrepant from structural language abilities.4
A. Persistent difficulties in the social use of verbal and nonverbal communication as manifested by all of the following:
1. Deficits in using communication for social purposes, such as greeting and sharing information, in a manner that is appropriate for the social context.
2. Impairment of the ability to change communication to match context or the needs of the listener, such as speaking differently in a classroom than on the playground, talking differently to a child than to an adult, and avoiding use of overly formal language.
3. Difficulties following rules for conversation and storytelling, such as taking turns in conversation, rephrasing when misunderstood, and knowing how to use verbal and nonverbal signals to regulate interaction.
4. Difficulties understanding what is not explicitly stated (e.g., making inferences) and nonliteral or ambiguous meanings of language (e.g., idioms, humor, metaphors, multiple meanings that depend on the context for interpretation).
B. The deficits result in functional limitations in effective communication, social participation, social relationships, academic achievement, or occupational performance, individually or in combination.
C. The onset of the symptoms is in the early developmental period (but deficits may not become fully manifest until social communication demands exceed limited capacities).
D. The symptoms are not attributable to another medical or neurological condition or to low abilities in the domains of word structure and grammar, and are not better explained by autism spectrum disorder, intellectual disability (intellectual developmental disorder), global developmental delay, or another mental disorder.
a Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright © 2013). American Psychiatric Association. All Rights Reserved.
SCD is likely to apply to some individuals who would have been classified as having PDD-NOS by DSM-IV-TR criteria but do not meet the DSM-5 criteria for ASD due to lack of restricted repetitive behaviors.4,5 The DSM-5 SCD concept expands upon research on pragmatic language impairment by including nonverbal communication, and further evaluation of the validity of the diagnosis is needed.4 Preliminary evidence suggests that this diagnosis identifies individuals who have marginally subthreshold autistic traits, rather than being qualitatively distinct from ASD.5
The Centers for Disease Control and Prevention (CDC) Autism and Developmental Disabilities Monitoring Network (ADDM) 2012 estimate of ASD prevalence in 8-year-old children was 1.46%, or 1 in 68.6 Analysis of a general population cohort of more than 3 million children using a commercial managed health care administrative database yielded a similar prevalence of 1.25% in the United States.7 Somewhat higher prevalence estimates have been described in survey studies, which are based on parent report of ASD diagnosis. For example, parents reported a current diagnosis of ASD in 2.0% of children aged 6 to 17 years in the 2011–2012 National Survey of Children’s Health,8 and the rate of parent-reported lifetime diagnosis of ASD was 2.24% of children aged 3 to 17 years in the 2014 National Health Interview Survey.9 The estimated global prevalence of ASD is lower: 0.76% in the Global Burden of Disease Study 2010,10 although recent estimates based on national registry data in Sweden, Denmark, and Iceland were greater than 1%,11–13 and the highest recent prevalence estimate, 2.64% for 7- to 12-year-old children in 2005–2009, was from South Korea.14 Males are more commonly affected than females, by a ratio of 4:1 to 4.5:1 in most studies,6 although a 2017 meta-analysis of studies conducted since the introduction of DSM-IV and ICD-10 criteria concluded that the true ratio is closer to 3:1.15
Substantial increases in the estimated prevalence of ASD in the United States over the last 3 decades have been found in studies using special education and developmental services administrative data,16–18 national family surveys,8,9,19 and active public health surveillance conducted by the CDC ADDM Network.6 Similarly, studies using registry data in Denmark,20 Norway,21 Iceland,12 Sweden,11,22 Israel,23 and other countries have reported an increase in ASD prevalence. However, incidence data adequate for determining time trends are scarce, and there is controversy about whether the available prevalence data actually establish that there has been an increase in ASD.10,24–26 For example, a 2015 systematic review of epidemiological studies with Bayesian meta-regression analysis found that after accounting for methodological variations, there was no clear evidence of a change in estimated worldwide prevalence of DSM-IV-TR– defined autism spectrum disorders (autistic disorder, Asperger disorder, and PDD-NOS) between 1990 and 2010.10
If there has been an increase in prevalence, it is not clear whether there has been a true secular increase in incidence due to etiologic factors in addition to the clear contribution of nonetiologic factors such as changes in identification and diagnostic practices, variation in study methods, and increased public awareness and availability of services.6,10,20,22,25 Some studies provide evidence of diagnostic recategorization toward ASD and away from other diagnoses such as ID and language disorders.18,27–31
ASD is etiologically heterogeneous and, perhaps unsurprisingly, a unifying pathophysiology has not been identified for either the disorder as a whole or its core behavioral components. Although research aimed at elucidating the biological basis of ASD and related neurodevelopmental disorders is in its early stages, much progress has been made in the areas of genetics, neuroimaging, neurophysiology, and neuropathology.
Genetics and Genomics
Although clinically and etiologically heterogeneous, ASD is heritable, as demonstrated by family studies showing increased risk of ASD in siblings of affected individuals and twin studies documenting substantially higher concordance rates for monozygotic twins than for dizygotic twins.32–36 For example, a large population-based family study involving more than 2 million Swedish children, including 14,516 diagnosed with ASD, yielded a heritability estimate of 0.83.36 Heritability estimates range from 64% to 91%, according to a meta-analysis of twin studies involving 6,413 twin pairs.35
1.A large number of rare variants, each conferring significant risk
2.Polygenic risk conferred primarily by a large number of common variants, or polymorphisms, which individually confer very small risk but collectively contribute substantially to the phenotype and to heritability
3.Some combination of genotype-by-genotype interactions (epistasis), genotype-by-environment interactions, and epigenetic effects
Although common variants, epistasis, and environmental modification of genotype effects are thought to be important, these aspects of the genetics of ASD are still poorly understood.39,42,43 Genome-wide association studies and candidate gene association studies have not yet implicated replicable risk loci, likely due to small effect sizes and lack of statistical power.38,41,43 Epistasis is difficult to detect because of the need for very large sample sizes, and there is little evidence so far for environmental modification of genotype effects.39
In contrast, advances such as the development of microarray and next-generation sequencing technologies have resulted in identification of large-effect variants that appear to be causally associated with ASD, including copy number variants (CNVs), which are microdeletions or microduplications ≥1,000 base pairs in size that alter the dosage of genes, short insertions and deletions (indels), and single-nucleotide variants (SNVs).40–42,44 Pathogenic rare variants may arise de novo or be inherited as autosomal dominant, autosomal recessive, or X-linked mutations. Microarray and exome sequencing studies have established that although de novo and inherited rare variants of large effect size are collectively common, no individual pathogenic variant accounts for more than 1% of nonsyndromic cases of ASD.37,45–48
It is important to note that no specific mutation has been identified that is unique to ASD. Chromosomal microarray analysis (CMA) and whole exome sequencing (WES) studies in ASD cohorts and other populations have made it clear that there is substantial genetic overlap between ASD and other neurodevelopmental disorders, including ID, epilepsy, and schizophrenia. These disorders all are associated with increased CNV and single gene loss-of-function mutation burden, and individual pathogenic variants are not specific to one categorical diagnostic phenotype—the same pathogenic CNVs and SNVs have been detected in individuals with ASD, ID, epilepsy, schizophrenia, and other clinical presentations.49–55
In clinical practice, a genetic etiologic diagnosis may be suspected clinically and confirmed by targeted genetic testing, or, more commonly, it may be revealed by CMA or WES completed as a routine part of the evaluation of a patient with ASD in the absence of a clinically recognizable syndrome. Examples of some of the most common genetic syndromes and mutations, including SNVs and recurrent CNVs, that are causally associated with ASD are presented in Table 19.1.40,42,44,56–60 Proteins encoded by genes that have been implicated in ASD have a variety of biological functions, but a pattern of convergence on functional pathways involved in synaptic structure and function and transcription regulation/chromatin remodeling has emerged.38,40,42,59
Increased maternal and paternal age are independently associated with ASD risk, and there is evidence for a combined parental age effect as well; ASD risk increases when the difference between the parental ages is 10 years or more.61–63 At least part of the ASD risk associated with advancing paternal age is explained by an age-related increase in the rate of de novo loss-of-function mutations in the male germ cell; potential mechanisms mediating the effect of advancing maternal age are under investigation.64
Genetic syndromes often suspected clinically and confirmed by genetic testing (implicated genes in parentheses)
Recurrent CNVs commonly identified by whole genome chromosomal microarray analysis
Single gene mutations‘ including SNVs and small insertions or deletions identified by whole exome sequencinga
Angelman syndrome (UBE3A)
CHARGE syndrome (CHD7)
Cohen syndrome (VPS13B)
Cornelia de Lange syndrome (NIPBL, RAD21, SMC3, HDAC8, SMC1A)
Down syndrome/trisomy 21
Fragile X syndrome (FMR1)
Neurofibromatosis type 1 (NF1)
PTEN hamartoma tumor syndrome (PTEN)
Rett syndrome (MECP2)
Timothy syndrome (CACNA1C)
Tuberous sclerosis (TSC1, TSC2)
15q11.2-q13.1 (BP2-BP3) duplication
15q13.2-q13.3 (BP4-BP5) deletion
a In the case of NRXN1, a very large gene (1.1 Mb, 24 exons), large intragenic deletions may be detected by chromosomal microarray analysis.
Abbreviations: CNV, copy number variant; SNV, single-nucleotide variant.
Gene names: ADNP, activity-dependent neuroprotector homeobox; ANK2, ankyrin 2; ARID1B, AT rich interactive domain 1B (SWI1-like); ASH1L, ASH1 (absent, small, or homeotic)-like; CACNA1C, calcium channel, voltage-dependent, L-type, alpha-1c subunit; CHD2, chromodomain helicase DNA binding protein 2; CHD7, chromodomain helicase DNA binding protein 7; CHD8, chromodomain helicase DNA binding protein 8; DHCR7, 7-dehydrocholesterol reductase; DYRK1A, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A; FMR1, fragile X mental retardation 1; GRIN2B, glutamate receptor, ionotropic, N-methyl-D-aspartate 2B; HDAC8, histone deacetylase 8; KATNAL2, katanin p60 subunit A-like 2; MECP2, methyl-CpG-binding protein 2; NF1, neurofibromatosis 1; NIPBL, nipped-B-like; NRXN1, neurexin 1; POGZ, pogo transposable element with ZNF domain; PTEN, phosphatase and tensin homolog; RAD21, double-strand-break repair protein rad21 homolog; SCN2A, sodium channel, voltage-gated, type II, alpha subunit; SHANK3, SH3 and multiple ankyrin repeat domains 3; SMC1A, structural maintenance of chromosomes protein 1A; SMC3, structural maintenance of chromosomes protein 3; SUV420H1, suppressor of variegation 4–20 homolog 1; SYNGAP1, synaptic Ras GTPase activating protein 1; TBR1, T-box brain, 1; TSC1, tuberous sclerosis 1; TSC2, tuberous sclerosis 2; UBE3A, ubiquitin protein ligase E3A.
There is evidence that aspects of the prenatal environment such as exposure to maternal medications (eg, valproate), short interpregnancy interval, multiple gestation, maternal obesity, gestational diabetes, gestational bleeding, and infections (eg, rubella, cytomegalovirus, influenza) may be associated with increased risk of ASD.65–67 The case for in utero selective serotonin reuptake inhibitor exposure as a causal risk factor independent of the maternal conditions (eg, depression and anxiety) for which they are prescribed has not yet been proven.67 Perinatal factors such as prematurity, low birth weight, fetal growth restriction, intrapartum hypoxia, and neonatal encephalopathy also may be associated ASD risk.67–69 However, more research is required to determine whether these are independent risk factors because genetic susceptibility may be associated with both obstetric suboptimality and neonatal encephalopathy.
Although toxic environmental chemicals have not been proven to cause ASD, associations between some compounds such as organophosphates and certain other pesticides, metals, and volatile organic compounds and ASD risk at the population level have been published.66,67,70 Several US studies have suggested an association between ASD and prenatal exposure to traffic-related air pollutants,70–72 but it is difficult to exclude confounding from sociodemographic or other factors; a Swedish twin study and a collaborative study of 4 European population-based cohorts found no such association.73,74
Epidemiological studies have definitively refuted the idea that toxic effects of either the measles-mumps-rubella vaccine, mercury exposure via thimerosal-containing vaccines, or excessive burden on the immune system caused by a larger number of vaccines is responsible for the increased prevalence of ASD, and the weight of all of the available scientific evidence overwhelmingly favors rejection of the hypothesis that there is a causal association between immunizations and ASD.70,75–80
The potential role of epigenetic factors in the etiology of ASD is also an active area of investigation and speculation.81,82 Epigenetic modifications, such as DNA cytosine methylation and posttranslational histone modification, produce heritable changes in gene expression that do not involve a change in the DNA sequence. Abnormal patterns of DNA methylation and chromatin structure can result in altered morphology, physiology, and behavior, and some genetic disorders associated with ASD involve dysregulation of epigenetic processes during development. Examples include syndromes caused by mutations in genes encoding epigenetic regulators (eg, MECP2 in Rett syndrome and CHD7 in CHARGE syndrome) and syndromes caused by mutations in genes that are sensitive to alterations in their epigenetic regulation (eg, 15q duplication, Angelman, Prader-Willi, and fragile X).81,83 Epigenetic mechanisms are responsible for genomic imprinting, the process whereby certain genes are epigenetically marked during gametogenesis in a parent of origin specific manner so that gene expression is restricted to only one of the parental alleles.83,84 Imprinted genes tend to be particularly sensitive to changes in their epigenetic status, and alteration of the gene dosage often results in pathology.84 One of the most common cytogenetic abnormalities in patients with ASD is maternally derived duplication of the imprinted domain on chromosome 15q11-q13.85
It has been speculated that epigenetic alteration of gene expression by environmental factors may play a role in the etiology of ASD, but replicated examples of environmental epigenetic marks and evidence of causality are currently lacking.82,83 A small number of candidate gene studies and genome-wide analyses of DNA methylation in a variety of brain regions and peripheral tissues have provided preliminary evidence of alteration of DNA methylation in association with ASD or ASD-related traits. However, methodological issues and the absence of replication studies limit the conclusions that can be drawn from the existing literature.82,86,87
Because epigenetic modifications can be influenced by environmental factors, such as prenatal exposures and postnatal experience, they represent one interface between genes and environment. Although appealing because they provide a tangible link between genes and environment, changes to the epigenome are not the only mechanism by which environmental effects are mediated, and epigenetics should not be conflated with the broader category of environmental effects.83,88 In fact, biochemical cause-and-effect should be demonstrated to establish epigenetics as the mechanism of a proposed gene by environment interaction.83,88 Despite the limitations of the existing evidence, exploration of the role of epigenetic and other nongenetic modifications that alter gene activity without changing the DNA sequence is likely to be an increasingly active and potentially important area of etiologic research in ASD.
No uniform neuropathology has been identified, which is not surprising given the etiologic and phenotypic heterogeneity of ASD. The systematic neuropathological studies of postmortem brain tissue from individuals with ASD have been summarized in Supplemental Table 1 of the 2015 review by Chen and colleagues,38 available at www.annualreviews.org. Dysplasia, altered neurogenesis, and neuronal migration abnormalities have been described within the cerebral neocortex, limbic system structures including the hippocampus and amygdala, basal ganglia, thalamus, brainstem, and cerebellum.38,89 The vast majority of abnormalities described originate prenatally.89,90
Focal disruption of the normal laminar architecture, minicolumnar abnormalities, and variations in neuronal density are among the most common cerebral cortical abnormalities described.89,90 Reduced neuronal number and/or size, increased cell-packing density, and decreased complexity of the neuropil have been found in the hippocampus and amygdala, although not in all individuals.38 Microglial infiltration and activation and astrocytosis have been observed in cerebral cortex and cerebellum, and postmortem transcriptome studies have reported upregulation of genes enriched in activated microglia and astrocytes, implicating dysregulation of neuron-glia signaling and neuroinflammation.38,42 However, it is not yet clear whether these findings represent primary pathology or a reactive or secondary process.
Biomarkers are objectively measured biological characteristics that influence or predict the incidence or outcome of disease. Proposed biomarkers of ASD include head circumference growth trajectory; structural and functional magnetic resonance imaging (MRI) markers; electroencephalographic characteristics; eye tracking markers; genetic and biochemical markers in blood, urine, or brain tissue; placental pathology; and maternal autoantibody profiles. However, no biomarker has yet been shown to be clinically valuable.91–93 Despite the limitations of the existing data, the future of biomarker research in ASD is promising due to increasing availability of bioresources linked to phenotypic data, advances in laboratory and neuroimaging technology and data management, and increasingly collaborative discovery and validation efforts.93
– Early Brain Overgrowth and Neuroimaging Markers
Cross-sectional and longitudinal studies suggest that as a group, children later diagnosed with ASD have average or below-average head circumferences at birth, with abnormal acceleration in brain growth during the first 1 to 2 years of life leading to significantly above-average head circumferences and MRI brain volumes in toddlers, followed by a plateau in brain growth resulting in brain volumes that are not significantly different from controls in adolescence and adulthood.94,95 Although this raises the possibility that atypical patterns of brain growth might be used for early identification, rate of head growth did not predict which infants developed ASD in the first 3 years of life in a large, prospective study of high-risk infants.96
True brain overgrowth, defined as abnormally large brain size and abnormally rapid rate of brain growth, occurs in a minority of children with ASD. A systematic literature review and meta-analysis of 27 studies concluded that the prevalence of macrocephaly, defined as head circumference above the 97th percentile, in individuals with ASD was 15.7%.95 Some recent studies have suggested that when individuals with ASD are compared to locally recruited controls rather than commonly used historical growth reference norms such as those provided by the CDC, the data are equivocal with regard to the finding of early brain overgrowth.97 Additional research is needed to clarify the relationship between early brain overgrowth and ASD, whether it distinguishes ASD from other neurodevelopmental disorders, and to what extent it is part of generalized somatic overgrowth.97,98
Although there are many conflicting findings, structural MRI volumetric studies of infants and young children have most consistently demonstrated increases in total brain volume, cortical gray and white matter volume (particularly frontal, temporal, and cingulate cortex), extra-axial cerebral spinal fluid volume, and amygdala volume in groups of young children with ASD relative to controls.99–101 Longitudinal studies suggest that neuroimaging findings are dynamic, and most of these volumetric differences do not persist into adolescence or adulthood.100,101 Mean cortical thickness is somewhat increased in childhood in ASD but declines more rapidly than the typical decline that occurs in adolescence, resulting in decreased mean cortical thickness in adulthood, particularly in the frontal lobes.101,102 Diffusion tensor imaging studies suggest age-dependent abnormalities of white matter microstructure, organization, and integrity based on metrics such as fractional anisotropy and mean diffusivity.99,101 Cross-sectional studies suggest that reduced fractional anisotropy and other measures of white matter microstructure persist into adolescence and adulthood, particularly in the corpus callosum, cingulum, and white matter tracts connecting aspects of the temporal lobe.100,103
Functional MRI (fMRI) studies have shown that ASD is associated with differences in activation of various brain regions relative to controls on tasks assessing motor skills, visual processing, executive functions, language, and basic and complex social processing skills.99,104 The authors of a meta-analysis and systematic review noted some common themes across task domains, including lack of preference for social stimuli, lack of modulation in response to task demands or intensity of stimuli, and decreased activation of areas of the prefrontal cortex generally recruited for executive functions (visual-spatial systems are favored instead).104 Most studies have identified evidence of task-dependent and resting state functional hypoconnectivity across a wide variety of brain areas in association with ASD, but other studies provide evidence of short range hyperconnectivity, particularly between subcortical regions and sensory cortices.104,105 The evidence for functional underconnectivity is strongest for long-range, frontal-posterior networks.99,104,105
Machine learning strategies including multivariate pattern classification have demonstrated that individuals can be classified categorically as having ASD with statistically significant accuracy using structural MRI and fMRI, and there is some evidence that they can predict the severity of symptoms (a quantitative or dimensional classification), but these methods have not yet been validated for clinical use.106,107
– Electrophysiological Markers and Eye Tracking
Electrophysiological techniques such as auditory brainstem response, electroencephalography (EEG), and event-related potentials allow precise temporal discrimination, and magnetoencephalography allows fine resolution in both time and space. Although the evidence has not yet established the utility of any marker in clinical practice, studies using these techniques have identified electrophysiological correlates of abnormalities in low-level and higher cognitive auditory and visual processing (including language processing and face processing), somatosensory response, multisensory integration, recognition memory, selective attention, attentional shifting, and neural connectivity in association with ASD.108–111 Resting-state and task-related quantitative EEG measures such as spectral power, complexity, and coherence are continuous and relate to typical development, making them good candidates for biomarker status.109,110,112 EEG spectral coherence loading patterns, for example, have been shown to differentiate between children with ASD and typically developing children with a high degree of success, but their ability to discriminate ASD from other neurodevelopmental disorders and their clinical relevance remain to be investigated.113
ASD is characterized by early emerging impairments in social attention, and eye tracking technologies have been used to demonstrate decreased fixation on the eyes’ region of the face and increased fixation on the mouth and background elements, as well as preliminary evidence that infants later diagnosed with ASD exhibit a decline in eye fixation between the ages of 2 and 6 months.114–117
– Biochemical, Gene Expression, and Other Tissue Markers
The biochemical markers most consistently reported to differentiate groups of individuals with ASD from controls include increased platelet serotonin level, decreased plasma melatonin and urine melatonin sulphate, indicators of increased oxidative stress or altered redox status, and markers of altered immune response such as irregular cytokine profiles and central nervous system microglial activation.91,92,93,118 Unlike variations in DNA sequence, which are largely fixed across tissues throughout the life span, the amount of RNA transcribed from each gene is tissue specific and varies developmentally and in response to environmental changes. Studies of gene expression in ASD are in their infancy and the results have varied widely, but several have reported upregulation of genes involved in immune and inflammatory responses in blood and postmortem brain tissue.119,120 Efforts to classify ASD risk based on gene expression profiling are preliminary, and it has been noted that the genes included in the classification panels derived by 2 different research groups do not overlap.121,122
Increased frequency of trophoblast inclusions relative to controls has been documented retrospectively in the placentas of children with ASD and prospectively in the placentas of children at risk for ASD based on having an affected sibling.123,124 However, trophoblast inclusions also have been identified in association with chromosome aneuploidy and placenta accreta, and further investigation is needed to determine the predictive value in regard to ASD and other neurodevelopmental outcomes.93,125 The pathogenic role of circulating maternal antibodies directed to fetal brain tissue and the potential value of maternal antibody panels as biomarkers of ASD also are active areas of investigation, but clinical value has not been established.92,126–130
ASD is defined clinically by the core impairments, which contribute to the DSM-5 diagnostic criteria in Box 19.1. However, no single specific behavior or deficit is pathognomonic for ASD and, although not part of the diagnostic criteria, other features such as cognitive and motor deficits, maladaptive behaviors, and associated medical problems have a dramatic impact on adaptive functioning and are also important aspects of the clinical presentation.
ASD is characterized by early onset, clinically significant impairment in social communication and other reciprocal social behavior and restricted and repetitive patterns of behavior, interests, and activities (Box 19.1).2 By definition, these symptoms interfere substantially with functioning and do not simply reflect coexisting ID. Clinical features of ASD, as elaborated in Boxes 19.4 and 19.5, vary with age, developmental level/ intellectual ability, and severity of the condition.
– Social Communication and Social Interaction
Pervasive and persistent impairment in reciprocal social behavior that is not accounted for by developmental level (or mental age) is a defining feature of ASD; deficits in the development and understanding of social and emotional reciprocity, nonverbal communicative behaviors, and interpersonal relationships are required for diagnosis2 (Box 19.1).
As infants and toddlers, children with ASD may not smile responsively or adopt a posture conveying anticipation and readiness or desire to be picked up. Young children with ASD typically lack developmentally appropriate joint attention (JA), which is coordinating attention with another individual to an external focus, showing social engagement and awareness of the partner’s mutual interest.131,132 JA behaviors can be receptive, (eg, responding by following the direction of eye gaze and gestures of others) or expressive (eg, initiating JA by using eye contact and gestures to direct the attention of others to an object or event of interest for the purpose of sharing their experience). Both are commonly delayed in children with ASD; however, initiation of JA for the purpose of sharing interest and enjoyment/positive affect rather than requesting is particularly atypical.131 JA ability is an important precursor and predictor of language and theory of mind, an important component of empathy.131,133 Reciprocal social behaviors such as seeking to share enjoyment with others, recognizing and reacting to the mental states of others, and forming reciprocal friendships that go beyond classroom or parent-arranged interactions are limited, even in older children.134 Even highly functioning adolescents and adults with ASD typically have difficulty navigating social interactions when it is necessary to make accurate inferences about other people’s beliefs, motivations, goals, and emotional states.135,136
Wing and Gould137 described 3 types of social impairment exhibited by individuals with ASD: aloof, passive, and active but odd. Individuals in the first group, whose social impairment is most easily recognized, are generally aloof and indifferent to others, especially peers, but may accept physical affection from familiar people and enjoy physical play. Those in the passive group do not socially interact spontaneously but passively accept and even appear to enjoy approaches from others. The active but odd group includes people who make active social approaches that are naïve, odd, inappropriate, and one-sided. Stability of the social interaction subgroup classification varies with level of cognitive ability. Children with higher levels of cognitive ability may move, for example, from the aloof group in early childhood to the passive or active but odd group in adolescence, whereas those with severe or profound ID are more likely to remain aloof and indifferent to others.
Box 19.4. Clinical Presentation of Autism Spectrum Disorder: Social Communication and Interaction Impairment
Younger or More Severely Impaired Children
Older or Less Severely Impaired Children
Poor eye contact, gaze aversion Limited or absent responsive smiling Decreased sharing of joyful affect Marked lack of interest in other people
▶ Often aloof and indifferent, may prefer to be alone
▶ More interested in objects than people
▶ May bump into people as if the child did not see them or climb on them as if they were furniture
▶ Rather than being distant, some children display indiscriminate affection
Deficits in joint attention
▶ Lack of response when name is called
▶ Failure to follow the gaze and pointing gestures of others
▶ Failure to spontaneously alternate gaze between an object and another person
▶ Absent or limited attempts to draw the attention of others to objects or events for the purpose of sharing experiences (including lack of pointing for the purpose of showing, commenting, or sharing interest or enjoyment)
Lack of adjustment of behavior according to environment or social context
May not have any meaningful speech
Greater proportion of syllables with atypical phonation (eg, squeals, growls, and yells)
Delayed receptive and expressive language milestones
Increased idiosyncratic or inappropriate means of communication
▶ Self-injurious behavior, aggression, tantrums
▶ Immediate echolalia (eg, in response to questions)
Pronoun reversal (often “you” for “I” or “me”)
May label objects or actions but not use those words to make requests or answer questions
Delayed, decreased, or absent use of symbolic gestures (eg, waving, pointing, shaking head for “no,” nodding head for “yes,” depicting actions)
Persistent use of primitive motor gestures to communicate (eg, contact gesture of leading or pulling another’s hand)
Nonsequential acquisition of milestones (eg, early labeling of letters and numbers despite having a small vocabulary and not using words to make requests)
Early lack of interest in toys
Subsequent preoccupation with elementary sensory features of toys
▶ Feeling, mouthing, lining, spinning, arranging, hoarding, and carrying
Later appreciation of symbolic meaning, appropriate functional use
▶ Sequences of appropriate actions
▶ Impoverished, lacks typical creativity or variability
▶ Repetitious, mechanical
▶ Often precisely imitated from videos
Solitary and parallel play, often some interactive physical play
Difficulty with turn-taking in play
Delayed and impaired development of pretend play
Decreased or atypical eye contact
Difficulty forming developmentally appropriate friendships that involve a mutual sharing of interests, activities, and emotions
Socially immature and less independent than peers
▶ May be viewed as odd, eccentric, or “weird” by peers
▶ May initiate interactions in inappropriate, awkward, or stilted ways
▶ Lack of awareness of personal space
▶ Gullible, naive, lacking “common sense”
▶ Lack of modulation of behavior according to social context
Poor perspective-taking ability that may contrib- ute to inappropriate, offensive behavior
▶ Difficulty anticipating how another person will feel or what he or she might think
▶ Lack of cognitive aspects of empathy
▶ Difficulty knowing how to react to another person’s behavior or emotions
▶ Difficulty accepting that there might be multiple perspectives, not just a single correct perspective
Unusual vocabulary for age and/or social group
Difficulty answering open-ended questions
Dysprosody (atypical intonation, inflection, rhythm of voice)
▶ Singsong or cartoonish
Difficulty with initiation and closure of conversation and topic changes
▶ Failure to provide enough background information
▶ Tangential remarks
▶ Abrupt topic changes
▶ Difficulty maintaining conversation by elabo- rating or requesting more information
One-sided conversations that revolve almost exclusively around the individual’s intense interest or include irrelevant details
▶ Lack of reciprocal exchange (monologue-like)
▶ Inadequate clarification, vague references
▶ Topic preoccupation, perseveration
▶ Scripted, stereotyped discourse
Overly literal; difficulty understanding nonliteral forms of communication, such as idioms, metaphors, humor/jokes, sarcasm, and irony
Difficulty recognizing and resolving communication breakdowns; unresponsive to partner’s cues
Difficulty adapting style of communication to social situation
▶ Inability to infer expected degree of formality
▶ Excessively formal or pedantic style
Good memory for details, difficulty understanding themes
Lack of appropriate use of facial expression, gestures, and body postures to facilitate communication
Difficulty with flexible cooperative imaginative play, such as interactive role-playing with peers
May have difficulty tolerating losing at games or sports
May lack creativity and imagination
The severity of language impairment ranges from profound (eg, verbal auditory agnosia) to relatively mild (eg, pragmatic impairment), and the clinical features vary with age and developmental level (Box 19.4).138–140 Communicative speech is often delayed or absent in young children with ASD, and comprehension is impaired.139 Nonverbal communication is also impaired, so there is often little or no attempt to compensate by using facial expressions, gestures, or pantomime, especially in young children with ASD. Approximately 20% to 30% of individuals remain nonverbal or minimally verbal.139,141
Box 19.5. Clinical Presentation of Autism Spectrum Disorder: Repetitive Behavior/ Restricted Interests and Activities
Younger or More Severely Impaired Children
Older or Less Severely Impaired Children
Stereotyped, repetitive movements
▶ Hand-flapping, finger-flicking, rocking, spinning, jumping or prancing on toes; whole | body twisting or posturing, etc.
▶ Incorporation of objects (eg, lining, flipping, or tapping various objects; dangling and jiggling or twirling strings or cords)
▶ Self-injurious behavior (independent of situation, automatically reinforced)
Stereotyped, repetitive speech
▶ Delayed echolalia (scripted verses, reciting memorized phrases)
▶ Greeting rituals
Insistence on sameness
▶ Excessive distress with deviation from routines or small changes in environment
▶ Difficulty with transitions
▶ Extreme dietary selectivity
Very limited range of interests and activities
Strong, preoccupying attachment to unusual objects (often hard rather than soft)
Unusual sensory interests
▶ Visual fascination with lights or objects that move or spin
▶ Atypical visual inspection, lateral eye gaze
▶ Excessive smelling, licking, or touching of objects
Aversion or hyperreactivity to sensory stimuli
Distress, avoidance, ear-covering in response to certain sounds
Gagging in response to smells or tastes or even the sight of foods with certain textures
Tactile defensiveness, aversion to social touch or certain textures
Hyporeactivity to sensory stimuli
▶ Lack of response to certain sounds, especially human voice
▶ Apparent indifference to pain or temperature
▶ Increased tolerance of spinning or being upside down
Repetitive movements and compulsions
▶ Complex stereotyped motor mannerisms
▶ Touching, tapping, rubbing
▶ Ordering, hoarding
▶ Telling or asking
▶ Reciting of memorized dialogue
▶ Idiosyncratic phrases
Strong desire to maintain sameness
▶ Inflexible adherence to routines or rituals
▶ Rigid thinking patterns
▶ Difficulty accepting unexpected change
▶ Difficulty with transitions
▶ Overly selective diet
Excessively narrow or circumscribed scope of interests and activities
▶ Special interests of abnormal intensity and/or focus
▶ Unusual preoccupations
▶ Obsession with facts, details, or collections
Aversion to and avoidance of certain sensations
▶ Touch/textures (eg, tags in clothing, social touch)
Excessive smelling or touching of objects or people
Although structural language skills are extremely variable and may be normal in some individuals, echolalia, jargon, neologisms, and other unusual semantic and syntactic error patterns are more frequent among children with ASD than typically developing children or children with ID.139,142 Even among individuals with higher verbal skills, the language profile that emerges in childhood and persists into adulthood is characterized by unevenness, including poor comprehension relative to expressive language, persistence of certain morphological errors, semantic processing anomalies despite normal performance on vocabulary tests, and idiosyncratic word usage despite relatively intact articulation and syntax.139,142
Deficits in pragmatics, which is the ability to use language in context for social purposes, are universal in individuals with ASD.139,140 Even the most able communicators with ASD typically exhibit significant atypicality in conversational discourse, including poor topic maintenance, difficulty with turn-taking, failure to respond adequately to questions or comments, inclusion of non-contextual or socially inappropriate utterances, and difficulty recognizing and repairing a misunderstanding or unclear referent.139 Other common deficits involve understanding figurative and metaphorical language, making inferences, and resolving ambiguous language.139,140
Children with ASD typically exhibit deficits in functional and symbolic play, including delayed onset, decreased frequency, reduced diversity, and qualitative atypicality.143 Qualitatively, the play of children with ASD tends to be solitary, repetitive, stereotyped, and excessively focused on sensorimotor manipulation of objects rather than interactive, varied, flexible, imaginative, and creative (Box 19.4).
– Restricted, Repetitive Behavioral Repertoire
Restricted and repetitive behaviors (RRBs) include repetitive sensorimotor actions (eg, stereotyped motor mannerisms and repetitive manipulation of objects), insistence on sameness/behavioral rigidity (eg, resistance to change, compulsive adherence to nonfunctional rituals or routines), and circumscribed interests (eg, fascination/ preoccupation with one subject or activity that is abnormal in intensity or focus; Box 19.5).144,145 It is important to recognize that repetitive behaviors, including stereotyped movements and behaviors related to desire for sameness, occur in normal development and in individuals with other developmental disabilities or psychiatric conditions, although most are more prevalent and/or severe in children with ASD.146,147
In general, younger children are more likely to engage in repetitive sensorimotor actions, whereas older children are more likely to exhibit repetitive behaviors based on insistence on sameness/behavioral rigidity and circumscribed interests.144,145,148 As a group, RRBs commonly decline in adolescence and adulthood, although there is considerable variability.135 Stereotyped movements are more persistent in adolescents and adults with ASD who also have ID, whereas behaviors based on insistence on sameness and circumscribed interests tend to be more independent of age and IQ.144,149 However, even in highly functioning individuals, unusual preoccupations and circumscribed interests often interfere with social interaction. Conversely, in addition to being sources of pleasure and motivation, special interests may provide themes around which social activities can be developed and, potentially, opportunities for employment.150
Atypical reactivity to sensory input and unusual interest in sensory aspects of the environment were incorporated into the DSM diagnostic criteria for ASD for the first time in DSM-5; symptoms in this category can fulfil 1 of the 4 restricted and repetitive behavior criteria, 2 of which are required for diagnosis (Box 19.1).2 Sensory modulation symptoms have been defined as difficulties in regulating and organizing the type and intensity of behavioral responses to sensory input to match environmental demands and are categorized as follows: (a) over-responsivity, which is exaggerated, rapid onset, and/ or prolonged reactions to sensory stimulation; (b) under-responsivity, which is unawareness or slow response to sensory input; and (c) maladaptive sensation seeking, which describes craving of and interest in sensory experiences that are prolonged or intense. Examples include apparent indifference to pain or temperature (under-responsivity), distress and ear-covering in response to certain sounds (over-responsivity), and atypical fascination with visual inspection of lights or spinning objects (sensation-seeking), as well as others (Box 19.5). Unusual sensory responses are described more commonly in children with ASD than in typically developing children; the effect size of the difference is greatest for under-responsivity, followed by over-responsivity and then sensation seeking.151 Although they may diminish in later childhood and adolescence, atypical reactivity to and/or interest in environmental sensory input may persist through adulthood.151,152
Population-based studies suggest that approximately 20% of children with ASD experience loss of previously established language skills and/or social interest and engagement skills at a mean age of 21 to 24 months.153,154 Clinic-based samples and survey studies yield higher rates of reported regression (35%–40%).153 However, even the more accurate population-based studies are plagued by problems with variable and sometimes vague case definition and reliance on parent-reported skill loss without verification by rigorous clinical information gathering, and the prevalence of true regression may be substantially lower.155
Autistic regression may be gradual or sudden and may occur following typical development or be superimposed on preexisting atypical development.153,156 Some studies suggest that regression is associated with increased likelihood of ID and higher rates of certain RRBs (eg, stereotyped speech, insistence on sameness, sensory interests and/or behaviors), but there is no definitive consensus.154,156 Although there is evidence that epilepsy is more common in individuals with ASD who have a history of regression, this association appears to be driven by lower IQ.157,158
Historically, ID was thought to be present in 70% to 75% of children with ASD, but many recent studies suggest that the prevalence of ID among individuals with ASD is substantially lower (32%–55%).6,11,12,159 A systematic review and meta-analysis of male to female ratio in ASD included 24 epidemiological studies published between 1996 and 2015 that provided sufficient information to determine that the mean proportion of participants with IQ <70 was 48%.15
Individuals with ASD often display an unusual degree of unevenness in cognitive abilities, frequently including a significant discrepancy between verbal and nonverbal abilities, which can be in either direction (verbal<nonverbal or verbal>nonverbal), and/or isolated strengths that significantly exceed not only their own general level of ability but general population norms as well.160 A strong correlation between uneven intellectual development and autistic-like symptoms, including those outside of the clinical range for ASD, has also been reported.161 Although a high degree of variability between domains and subtests is common, a prototypical profile of cognitive strengths and weaknesses does not exist.160,162
IQ testing to identify verbal and nonverbal cognitive abilities and specific strengths and weaknesses is useful in educational planning for children with ASD, as it is for children with other disabilities. Although IQ is one of the most robust predictors of outcome for individuals with ASD, it is important to recognize that low IQ is more reliably predictive of a poorer outcome than high IQ is of a better outcome and that IQ, especially among higher-ability individuals, often significantly exceeds adaptive functioning in the community.160
Performance profiles also vary on standardized measures of academic achievement. Skills requiring primarily rote, mechanical, or procedural abilities are typically intact, but skills requiring more abstract reasoning, conceptualization, or interpretive analysis are often deficient.163,164 For example, a child with ASD may have very good phonological awareness and decoding abilities but poor reading comprehension. Because the types of skills emphasized in the early elementary grades play to their strengths in memorization and concrete tasks, such as decoding and numerical operations, young children with ASD may perform well academically. In later elementary and middle school grades, when comprehension, analytic interpretation, and abstract reasoning skills are emphasized, these children often struggle academically and require more supports.164,165
Neuropsychological theories that help to explain the behavior and cognitive performance profile of individuals with ASD are described in Table 19.2.167–171 Some neuropsychological theories suggest that cognitive impairments or biases, such as executive functioning and information-processing differences, underlie the behavioral manifestations of ASD throughout development.167 In contrast, social motivation and social cognition theories emphasize early emerging, core social deficits that precipitate a developmental cascade of disrupted social and communicative development. Although no single theory adequately explains all aspects of ASD, recognition of the fundamental deficits in social motivation, perspective-taking, cognitive flexibility, and the ability to process complex information and form a coherent global picture is very helpful for understanding the behavior of children with ASD and explaining it to parents and teachers.
Executive Functioning Impairment
Key impairment in higher-level cognitive skills (eg, working memory, planning, inhibition, cognitive flexibility, self-monitoring) that underlie independent, goal-oriented behavior important for social and adaptive functioning.
Deficit in using executive functions to go beyond automatic activities and plan and carry out an integrated course of action.
– Difficulty with creating strategies for behavior, making plans, shifting topics, maintaining a representation in working memory, solving tasks requiring ability to be flexible and innovative.
– Deficits on tasks such as the Tower of London, Tower of Hanoi, and Wisconsin Card Sorting Test.
Information Processing Impairment
Differential ability to process information that differs in kind (global/ featural) or level of complexity.
Atypicality at the level of whole-brain processing.
1. Weak central coherence
Limited drive for “central coherence” (meaningful wholes).
– Tendency to focus on details/featural elements and overlook broader contexts and global meaning.
– As a group, children with ASD are good at finding figures embedded in larger forms, completing jigsaw puzzles, and reproducing patterns with blocks.
– Approximately 20% have islets of special ability, or splinter skills.
– Intact local processing, impaired global processing.
2. Complex information Processing impairment
Overall information processing is reduced relative to general cognitive ability level.
Abilities and tasks most impacted are those that place the highest demands on information processing.
– Difficulty with memory for complex information
– Difficulty with higher-order integrative and interpretative aspects of language and concept formation
– Intact basic attention, sensory perception, associative memory, and language encoding and decoding abilities
The information processing disturbance is generalized and includes nonsocial cognition.
Many things that come naturally to typically developing children must be cognitively discovered by or explicitly taught to those with ASD using compensatory strategies.
Social Motivation Impairment
Innate, biologically based attenuation of responsiveness to social stimuli and motivation for social engagement is theorized to limit the child’s early social experiences, which negatively impacts normal experience- expectant neurodevelopmental processes that underlie the emergence of a wide variety of social communicative behaviors that are known to be impaired in ASD (eg, face processing, joint attention, social information processing).
– Failure to orient to social stimuli, such as human sounds, and to prefer human to nonhuman speech in infancy
– Impaired face recognition, emotion recognition from faces and from voices, and matching facial and vocal expressions of emotions
Social Cognition Impairment
Impairments in the capacity to represent and reason about the thoughts, beliefs, and emotional states of others
1. Theory of mind (ToM) deficit (mindblindness, mentalizing deficit)
Impaired ability to take the perspective of others and understand that other people have intentions, knowledge, and beliefs that may differ from their own.
– Delays and deficiencies in developmental tasks such as understanding relationships between mental states (eg, seeing leads to knowing), knowing that people can have “false beliefs” and “beliefs about beliefs,” recognizing faux pas, and understanding subtle and figurative aspects of speech such as idioms, irony, metaphor, and sarcasm
– Necessary for developing the ability to identify other people’s intentions based on their gestures, expressions, and speech and for understanding deception
– The cognitive component of empathy
2. “Extreme male” empathizing-systemizing profile
Empathizing: Capacity to predict and respond to the behavior of agents (usually people) by inferring their mental states (ie, cognitive empathy or ToM) and to respond with an appropriate emotion (affective empathy).
Systemizing: Capacity and drive to analyze or construct systems, which are governed by rules. Systemizing involves trying to identify the rules that govern the system to predict how that system will behave.
In both males and females with ASD, there is a profile of relatively low empathizing (explaining social communication and interaction deficits) and high systemizing (explaining the narrow interests, repetitive behavior, and insistence on sameness)—a more extreme form of the typical male pattern.
Abbreviation: ASD, autism spectrum disorder.
aThese theories and features are overlapping, not mutually exclusive.
In addition to the core impairments that define ASD and its neuropsychological characteristics, there are other common medical and behavioral features that impact clinical presentation and management.
– Motor Impairments
In addition to motor stereotypies, children with ASD often exhibit less distinctive motor abnormalities, including impairment in basic aspects of motor coordination (eg, postural control, gait, attainment of gross and fine motor skills), performance of skilled motor gestures (dyspraxia), and motor learning activities.172–174 A core feature of motor dysfunction in ASD seems to be excessive reliance on proprioceptive feedback and weak integration of visual feedback.174 Clinically, parents may be concerned about delayed attainment of motor milestones, clumsiness, toe-walking, or difficulty with handwriting. Neurological examination may reveal hypotonia, decreased postural stability, poor motor imitation abilities, and other subtle, neurological signs, such as slow speed, dysrhythmia, and increased overflow movements on timed movements of the hands and feet and stressed gait maneuvers. Tic disorders, including Tourette disorder, also occur with increased frequency in children with ASD and in their siblings.175–177
ASD is associated with increased risk of epilepsy, with bimodal peaks in age of onset in early childhood and adolescence.158,178 All seizure types occur in individuals with ASD, but complex partial seizures, with or without secondary generalization, are reported to be more common than primary generalized seizures.178 The reported prevalence of epilepsy in ASD ranges widely, with the largest studies reporting ranges of 12.5% to 37% in clinic-based samples157,179,180 and 6.6% to 22.5% in population-based samples.181–183 In a large cross-sectional study combining 3 clinical samples and 1 population-based sample (n=5,815), the best estimate of the cumulative prevalence of epilepsy in ASD through age 17 years was 26%.157
The most robust risk factors for epilepsy in children and adolescents with ASD are low IQ and older age.158,178,184 Although the prevalence is highest in individuals with severe ID and those with identified genetic etiologies, even the subgroup with idiopathic, high-functioning autism has a rate of epilepsy that is substantially higher than the rate in the general population.178 The rate of medically refractory epilepsy may be increased in this population as well.185 In addition, many children with ASD have interictal epileptiform activity on EEG, especially during sleep, even though they have not had definite clinical seizures.178,186 The clinical significance of the increased rate of interictal EEG abnormalities is unclear, however, and very little information has been published to support the idea that epilepsy or epileptiform EEG abnormalities cause ASD or have treatment implications.158,178,186,187
– Neurobehavioral Symptoms/Coexisting Psychiatric Disorders
Neurobehavioral features that are commonly associated with ASD and cause significant impairment and distress include irritability, anger outbursts, aggression, self-injurious behavior, property destruction, elopement or wandering, sleep disturbance, mood instability, anxiety, hyperactivity, impulsivity, inattention, and other disruptive behaviors or manifestations of emotional dysregulation. Although these problem behaviors are not core features of ASD, they commonly interfere with functioning in school, at home, and in the community, and they contribute substantially to the burden on families.188–194 In some cases, the diagnosis of a coexisting psychiatric disorder can be reasonably made, although modifications of the diagnostic criteria may be necessary when there is significant intellectual impairment. Psychiatric diagnoses reported to co-occur with ASD in children and adults include attention-deficit/hyperactivity disorder (ADHD) (28%–44%), anxiety (42%–56%), depression (12%–70%), psychotic disorders (12%–17%), tic disorders (14%–38%), and oppositional defiant disorder (16%–28%).194
Sleep problems are reported in 40% to 80% of children with ASD (versus 25%–40% of typical controls), and they are common at all ages and levels of intellectual ability.195 Sleep disturbances are burdensome to children with ASD and their family members due to their prevalence, chronicity, and impact on emotional and behavioral problems. Insufficient sleep is associated with exacerbation of core ASD symptoms (RRBs and social communication and interaction difficulties) as well as tantrums, self-injurious behavior, aggression, and other disruptive behaviors.195 Children with ASD experience a variety of sleep problems, including bedtime resistance, prolonged sleep-onset latency, decreased sleep efficiency, increased waking after sleep onset, reduced total sleep time, and daytime sleepiness.195,196 Behavioral factors, including inadequate sleep hygiene, maladaptive sleep-onset associations (eg, being held until asleep), and problems with limit-setting, are common, but ASD-associated melatonin or GABA abnormalities, coexisting neurological or psychiatric disorders (eg, epilepsy, ADHD, and anxiety), other medical problems (eg, gastroesophageal reflux), and adverse effects of medications may also contribute to disordered sleep.195,196 Occasionally, other sleep disorders, such as obstructive sleep apnea, parasomnias, and periodic limb movements of sleep, are identified.
– Gastrointestinal and Feeding Problems
A meta-analysis of 15 methodologically suitable studies involving 2,215 children indicated that children with ASD experience significantly more general gastrointestinal (GI) symptoms, diarrhea, constipation, and abdominal pain than comparison groups.197 The available data were not sufficient to determine whether symptoms often suggestive of organic GI pathology, such as gastroesophageal reflux, gastroenteritis, inflammatory bowel disease, or food allergies, occur more frequently in children with ASD than in controls, and there is no evidence suggesting a unique GI pathophysiology in ASD.197,198 The contribution of behavioral factors such as delayed bowel training, rigidity about toileting routine, sensorimotor issues, and food selectivity to the observed higher prevalence of symptoms in children with ASD is unclear but plausibly substantial.197
These symptoms may impact behavior substantially. For example, in a well-characterized sample of children who participated in 2 Research Units on Pediatric Psychopharmacology Autism Network medication trials, the subgroup of children with GI problems (23%) had greater symptom severity on measures of irritability, anxiety, and social withdrawal than those without GI problems, and their irritability was less likely to respond to treatment with risperidone.199 GI problems may not be obvious in some children with ASD due to communication deficits and/or under-responsivity to sensory input but should be considered in cases of unexplained irritability/agitation, food refusal, self-injury, aggression, sleep disturbance, or other problem behavior that is new or represents a significant exacerbation of baseline status.197,198
Feeding problems, including food selectivity (often based on texture, color, or temperature), rituals around food presentation, and compulsive eating of certain foods, are common, as are behaviors associated with food refusal (eg, holding food in the mouth, volitional gagging, emesis), rumination, and pica.200–202
Surveillance and Screening
Surveillance is the ongoing process of actively identifying children who may be at risk for developmental disorders, and screening is the use of standardized tools at specific intervals to support and refine risk. The American Academy of Pediatrics (AAP) has established guidelines for developmental surveillance and screening (see Chapter 9, Developmental and Behavioral Surveillance and Screening Within the Medical Home).203 Surveillance is a continuous process that should occur at every preventive care visit during childhood and include the following components: eliciting and attending to the parents’ concerns, maintaining a developmental history, making accurate and informed observations of the child, identifying the presence of risk factors and protective factors, and documenting the process and findings.203
The AAP recommends general developmental screening using a broadband measure for all children at ages 9, 18, and 24 to 30 months or at any time concerns are raised by a caregiver or primary pediatric health care professional.203 In addition, specific screening for ASD is recommended at the 18- and 24-month visits and whenever parents’ concerns are raised or other risk factors are identified through general developmental surveillance and screening.138 The 2007 recommendation for universal screening for ASD in toddlers was based on the recognition that symptoms can be observed in very young children and mounting evidence that early identification leads to early intervention and improved outcomes.138,204 The US Preventive Services Task Force (USPSTF) completed a literature review and concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for ASD in young children (ages 18–30 months) for whom no concerns of ASD have been raised.205 This is not a recommendation against universal screening in this age group, but it is also not a recommendation for the practice. The AAP has affirmed its recommendation for universal screening for ASD at the ages of 18 and 24 months, and several strong commentaries have supported the approach and criticized aspects of the USPSTF interpretation of the data.206–209
A variety of general developmental (broadband), language-specific, and autism-specific screening tools have been shown to identify children of different ages who are at risk for ASD. Some examples of parent-completed screening measures that may be appropriate for use in primary care are described in Table 19.3. The Infant-Toddler Checklist, which is part of the Communication and Symbolic Behavior Scales Developmental Profile, is a screen for communication deficits in 6- to 24-month-olds that has been shown to identify ASD, language delay, and other developmental delay at age 12 months.210 The Modified Checklist for Autism in Toddlers, Revised, with Follow-Up (M-CHAT-R/F) is the most commonly used tool for screening toddlers for ASD. It consists of a 20-question caregiver form as the first stage and, when the score is elevated, a brief, structured interview administered by a health care professional. Among children who fail the M-CHAT-R/F in community primary care settings, 50% are ultimately diagnosed with
Table 19.3. Examples of Parent/Caregiver-Completed Screening and Assessment Instruments
Time to Complete (min)
Screening Instruments (potentially appropriate for use in unselected populations)
Infant-Toddler Checklist (ITC)a
Modified Checklist for Autism in Toddlers (M-CHAT-R/F)b
Parent’s Observations of Social Interactions (POSI)c
Pervasive Developmental Disorders Screening Test-II Primary Care Screener (PDDST-II PCS)
Autism Spectrum Quotient-Children’s Version (AQ-Child)
Childhood Autism Spectrum Test (CAST)
Social Communication Questionnaire (SCQ)
Autism Spectrum Screening Questionnaire (ASSQ)
Assessment Instruments (commonly used in diagnostic evaluations and for monitoring purposes)
Autism Spectrum Rating Scales (ASRS)
Children’s Communication Checklist (CCC-2)
Gilliam Autism Rating Scale (GARS-3)
Social Responsiveness Scale (SRS-2)
a The ITC is part of the Communication and Symbolic Behavior Scales Developmental Profile (CSBS-DP).
b The original M-CHAT is a parent/caregiver form. The M-CHAT, Revised, with Follow-Up (M-CHAT-R/F) includes a caregiver form as the first stage and, in some cases, a structured survey administered by a health care professional.
c The POSI is part of a comprehensive primary care screening instrument, the Survey of Wellbeing of Young Children (SWYC).
ASD and 98% have an actionable developmental concern.207,211 If a screening test is positive (“failed”), suggesting risk of ASD, the child should be simultaneously referred to the early intervention program or school evaluation team for services and to a specialist or team for comprehensive diagnostic evaluation.138 Audiological evaluation is often warranted, particularly in a young child with delayed receptive and expressive language development.
The diagnostic evaluation will vary depending on the availability of local resources and clinician preferences. An interdisciplinary team specializing in ASD and other developmental disabilities may be ideal, but often these are not available outside of major medical centers, and waiting lists may be very long because of high demand. Many communities will have at least one expert who is capable of interpreting and integrating information from various disciplines and comfortable with making the diagnosis of ASD even if there is not an interdisciplinary team that meets in person. This may be a developmental-behavioral or neurodevelopmental pediatrician, child and adolescent psychiatrist, pediatric neurologist, or pediatric psychologist, for example.
The clinical standard of care for ASD diagnosis is expert clinician evaluation and application of the current DSM or ICD criteria (DSM-5, ICD-10; ICD-11 ). There is considerable overlap in symptoms among developmental and behavioral diagnoses, especially in very young children and those with ID or language impairment, and it is important for the diagnostician to consider the alternate explanations for observed symptoms. Standardized rating scales, such as the assessment instruments presented in Table 19.3, which are completed by parents, teachers, or other intervention professionals, may be used to gather and quantify information. In the hands of trained clinicians, diagnostic instruments such as those presented in Table 19.4 help to operationalize the diagnostic criteria and inform clinical judgment.138,212,213
Table 19.4. Diagnostic Evaluation Tools
Autism Diagnostic Interview—Revised (ADI-R)
Structured caregiver interview
Diagnostic Interview for Social and Communication Disorders (DISCO)
Structured caregiver interview
Autism Diagnostic Observation Schedule (ADOS)
Semi-structured direct observation/elicitation
Childhood Autism Rating Scale (CARS)
Combination interview and unstructured observation/elicitation
1.Caregiver interview. This includes a thorough developmental and behavioral history (including milestone attainment and report of current abilities), medical history, social history, and family history (at least 3 generations). Structured interview tools (eg, Autism Diagnostic Interview-Revised, Diagnostic Interview for Social and Communication Disorders) are informative but are often impractical in clinical settings because of time constraints. Standardized rating scales completed by parents/caregivers and teachers or other professionals, such as the assessment instruments described in Table 19.3, are commonly used to quantify ASD symptoms and compare them to normative populations.
2.Review of pertinent existing data. The pertinent medical and educational records should be reviewed, especially any available standardized testing completed by psychologists, speech-language pathologists, occupational therapists, early intervention evaluators, or others. Although not necessary for categorical diagnosis, it is helpful to note the results of any previous etiologic investigations and other pertinent tests that have been completed (eg, genetic testing, audiometry, central nervous system imaging).
3.Direct clinical assessment. This includes standardized developmental and psychological testing (appropriate for age and level of ability) and neurobehavioral observation/ elicitation. Receptive and expressive language, nonverbal intellectual ability, and functional adaptive behavior should be measured. Administration of standardized ASD-specific direct observation/elicitation instruments (eg, Autism Diagnostic Observation Schedule, Childhood Autism Rating Scale) is desirable. When the evaluating diagnostician is a physician or advanced care practitioner, physical examination targeting the neurological examination and evaluation for dysmorphic features and other clues to etiology should be included.
4.Integration of information and determination of DSM-5 (or ICD-10/11) categorical diagnoses. Clinical judgment is informed by the caregiver interview and direct clinical assessment, often including information from ASD-specific diagnostic instruments and by input from other sources (eg, narrative reports or standardized rating scales completed by a teacher, paraprofessional aide, or therapist).
The goal should not be to simply decide whether the child has ASD or not but to determine the child’s developmental diagnoses, whatever they may be, and the diagnostic summary should include domain-specific information regarding the child’s level of functioning/severity of impairment.212,213 Children who have been diagnosed with ASD also require periodic formal reevaluation because their strengths, weaknesses, and educational needs often change even if the ASD diagnosis does not.212
The role of primary pediatric health care professionals does not end with diagnosis. Comprehensive management of patients after the diagnosis of ASD includes conducting an etiologic investigation; providing genetic counseling; promoting general health and well-being through effective longitudinal health care within a medical home; guiding families to effective educational, behavioral, and medical interventions; and alleviating family distress by providing support, education, and access to resources.214,215 Primary pediatric health care professionals may take part in any or all of these duties in addition to making referrals and coordinating subspecialty care and other services.
Currently, there is no single consensus approach to etiologic evaluation for children newly diagnosed with ASD. In recent years the availability of new methods of genetic testing has progressed so rapidly that the publication of state-of-the-art guidelines by professional organizations lags behind. Therefore, the recommendations in this chapter reflect the authors’ assessment of the current literature rather than strict adherence to guidelines published previously by various professional organizations.
– Genetic Testing
Identifying a genetic etiologic diagnosis may allow clinicians to provide more accurate prognostication and recurrence risk counseling, identify and treat or prevent medical comorbidities, guide patients and families to condition-specific resources and supports, and, in some cases, refine treatment options.216–224 For these reasons, there is consensus agreement that a genetic evaluation should be offered to every person with ASD.225–228 However, surveys suggest that that only about 33% of children with ASD in the United States have undergone any genetic testing.229–233
CMA reveals a definitively pathogenic CNV in 5% to 14% (median 9%) of individuals with ASD in clinical cohorts.46,234–242 These numbers do not reflect variants of uncertain significance, many of which are likely to subsequently be determined to be pathogenic; when variants of uncertain significance are included, the reported CNV detection rate in these studies is 17% to 24%. Large, clinical whole exome sequencing studies have consistently identified a molecular diagnosis in 26% to 29% of individuals for whom neurodevelopmental disorders were the primary indication for testing.243–245 Studies restricted to clinically ascertained samples of patients with ASD and analyses of ASD subgroups within the large, laboratory-based samples have reported WES yields of 8% to 20%.46,48,245 There is emerging evidence that WES is not only diagnostically useful but also cost-efficient in the etiologic evaluation of children with neurodevelopmental disorders, including ASD.246–249
Fragile X Testing
The combined yield of fragile X testing in 6 recent large studies was 9 full mutations in 1,984 individuals tested (0.45%), and 22% of those found to have fragile X syndrome were female.237,238,241,250–252 Because males and females with fragile X syndrome are identified fairly frequently in ASD cohorts, testing is relatively inexpensive, and the condition has important genetic counseling implications due to always being inherited, it is reasonable to routinely test both males and females with ASD for fragile X syndrome, at least until more data become available to clarify the issue. DNA testing for fragile X syndrome is ordered as a separate test because pathogenic repeat expansions such as the CGG trinucleotide repeat expansion that is responsible for fragile X syndrome are not detected on CMA or WES.
Approach to the Genetic Etiologic Evaluation
When the diagnosis of ASD is made by a physician or a diagnostic team that includes a physician, the physician may also take responsibility for the etiologic evaluation. If the diagnosis is made by a psychologist or by a physician who does not provide this service, referral to a medical geneticist is appropriate. In some cases, the primary pediatric health care professional may take on this role. In any case, clinicians should only order tests that they are capable of explaining (ie, providing pretest counseling and obtaining informed consent) and interpreting, although full interpretation of abnormal or equivocal results may involve referral to an appropriate subspecialist (eg, a medical geneticist). Pretest counseling involves describing the nature of the test, including potential outcomes, and addressing points such as possible impact on other family members. Most pediatric subspecialists who diagnose ASD, and many general pediatricians, are comfortable with explaining, ordering, and interpreting fragile X testing and CMA. WES is typically ordered by a medical geneticist or, in some cases, another pediatric subspecialist with the appropriate expertise, and a genetic counselor is likely to be involved in the vast majority of cases.
An etiologic search begins with a careful medical and family history and physical examination. Important aspects of the physical examination include assessment for abnormal growth (including head circumference), major and minor congenital anomalies, evidence of visceral storage, skin manifestations of neurocutaneous disorders or mosaicism, and neurological abnormalities.228 When a specific syndrome or metabolic disorder is suspected, the next step is to proceed with the appropriate targeted testing or refer to medical genetics. For example, a child presenting with ASD and microcephaly, ptosis, anteverted nares, and cutaneous 2–3 toe syndactyly should have a 7-dehydrocholesterol level measured to test for Smith-Lemli-Opitz syndrome. Similarly, marked macrocephaly and pigmented macules on the glans penis in a child diagnosed with ASD would warrant PTEN sequencing and deletion/duplication analysis. If there is no strong suspicion of a particular diagnosis or testing for suspected diagnoses has been completed and is negative, CMA and fragile X DNA analysis are recommended. If these are unrevealing, clinical WES is recommended. These steps are outlined in Box 19.6.
Box 19.6. Genetic/Genomic Etiologic Investigation in Patients With Autism Spectrum Disorder
1. History, including 3-generation family history, and physical examination
— If a specific syndrome diagnosis or metabolic disorder is suspected, proceed with targeted testing.
— Otherwise, proceed to step 2.
2. Whole-genome chromosomal microarray analysis (CMA) and fragile X analysis
— If these studies do not reveal the etiology, proceed to step 3.
3. Whole exome sequencing (WES)