GeneTest Review | Published:

Autism spectrum disorders—A genetics review

Genetics in Medicine volume 13, pages 278294 (2011) | Download Citation

Disclosure: The author declares no conflict of interest.


Abstract: Autism is an etiologically and clinically heterogeneous group of disorders, diagnosed solely by the complex behavioral phenotype. On the basis of the high-heritability index, geneticists are confident that autism will be the first behavioral disorder for which the genetic basis can be well established. Although it was initially assumed that major genome-wide and candidate gene association studies would lead most directly to common autism genes, progress has been slow. Rather, most discoveries have come from studies of known genetic disorders associated with the behavioral phenotype. New technology, especially array chromosomal genomic hybridization, has both increased the identification of putative autism genes and raised to approximately 25%, the percentage of children for whom an autism-related genetic change can be identified. Incorporating clinical geneticists into the diagnostic and autism research arenas is vital to the field. Interpreting this new technology and deciphering autism's genetic montage require the skill set of the clinical geneticist including knowing how to acquire and interpret family pedigrees, how to analyze complex morphologic, neurologic, and medical phenotypes, sorting out heterogeneity, developing rational genetic models, and designing studies. The current emphasis on deciphering autism spectrum disorders has accelerated the field of neuroscience and demonstrated the necessity of multidisciplinary research that must include clinical geneticists both in the clinics and in the design and implementation of basic, clinical, and translational research.


Autism is an etiologically and clinically heterogeneous group of disorders, collectively referred to as the “autism spectrum disorders” (ASDs).1 First described in the early 1940s almost simultaneously by psychiatrists Kanner2 in the United States and Asperger3 in Austria, autism remained mostly unnoticed outside of psychiatry through the 1980s. More than mental retardation and gender disorders, autism suffered from the extreme environmental fixation of the 1960s. Mothers were blamed for their children's illness and branded as “refrigerator mothers” being told that their children failed to develop social relationships because of their coldness; many children were placed in horrid institutions using aversive treatments. Not surprisingly, families developed a marked and deserved distrust of physicians and medicine in general, which still seems to influence responses to medical recommendations.

By the late 1980s, twin studies that compared concordance for autism in identical and fraternal twins showed, that contrary to previous dogma, autism was a highly genetic disorder with heritability indices of 0.85–0.92.4 Smalley et al.5 reviewed this work and reported an average concordance for identical twins of 64% vs. 9% for fraternal twins. Family studies, most notably the University of California, Los Angeles-University of Utah study reported significant sib recurrence risks in large Utah families; the latter sib recurrence risk was 8.6%, and for families with two or more affected children, the recurrence risk approached 35%.6 The third indicator that autism is genetically determined comes from finding that a comprehensive genetics evaluation can reveal a chromosomal or Mendelian cause or at least predisposition in 15% to 40% of children who fit ASD behavioral diagnostic criteria.7

Understanding the genetics of autism has proven difficult. Although the etiologic and clinical heterogeneity is universally recognized, in practice, many studies still fail to take this into account. When considered as a single entity, autism does not fit known inheritance patterns, and although this could just be a product of the unrecognized etiologic heterogeneity, a number of tantalizing pieces of data indicate that the geneticist will need to incorporate new and emerging data from neuroscience, as well as genetics to fully understand the causes of autism. In this review, I will summarize what we know at this time about the genetics of autism and suggest some of the reasons medical geneticists need to be part of the team involved in both the diagnosis and research into causes of the ASDs.


The growing number of children being diagnosed with autism has raised enormous concern from parents, physicians, and scientists fearing that some environmental toxins have emerged to cause an autism epidemic. Before 1990, the general population prevalence for autism was considered steady at 4–5/10,000 (1/2,000–1/2,500).8 However, during the 1990s, studies of preschool children in Japan, England, and Sweden reported increasing prevalence rates for classical autism of 21–31/10,000 (1/476–1/323).9,10 By 2005, Chakrabarti and Fombonne11 reported a prevalence rate of 22/10,000 (1/455) for classic autism and 59/10,000 (1/169) for all pervasive developmental disorders (PDDs) in children younger than 6 years. Similar advances were reported in the United States, starting with the Center for Disease Control case-finding study in Brick Township, New Jersey, which reported prevalence at 40/10,000 (1/250) for classic autism and 67/10,000 (1/149) for all PDDs.12 Recent studies in the United States reported the diagnosis of an ASD in 1/91 3- to 17-year olds13 and 1/110 8-year-old children.14

Virtually all epidemiologic analyses, at this time, indicate that this apparent “autism epidemic” does not reflect a true increase in the incidence of ASD but rather is attributable to increased awareness by both the public and professionals, leading to more complete case finding together with broadening of the diagnostic criteria.1519 Studies finding the greatest increase in ASDs also observed lower rates of mental retardation. Only 30% of children with PDDs ascertained by Chakrabarti and Fombonne11 were mentally retarded compared with 70% of children in earlier studies. This is consistent with the scenario that higher-functioning children with less language impairment and fewer aggressive behaviors had not been counted in older epidemiologic surveys. Nevertheless, ongoing research in this area is required. The recent update from an ongoing epidemiologic surveillance of autism indicated that the rise of autism in California shows no sign of plateauing. They concluded that earlier age at diagnosis and inclusion of milder cases accounted for more than two thirds of the increase but stated that the extent to which the continued rise might represent a true increase in the occurrence of autism remains unclear.20


ASDs develop before the age of 3 years. Infants typically do not care to be held or cuddled and do not reach out to be picked up. Often they are “colicky” and hard to console, typically quieting more readily when left alone. They may avoid and fail to initiate eye contact or stare into space. Despite early signs, children with ASD often do not come to medical attention until after the second year when language delays are obvious.

For most children, the onset of ASD symptoms is gradual; however, approximately 30% have an obvious “regressive” onset. These children begin to speak and then, either gradually or precipitously, lose language and become distant. Within a matter of days, the child may refuse to make eye contact and stop responding to his/her name. Repetitive movements may develop immediately or not until the child is 3 or 4 years of age. Although it has been debated whether these children are well and then become damaged by some exogenous exposure, the best evidence, including retrospective analysis of first birthday videotapes and neuropathologic studies, suggests their regressive course is genetically determined.2125

Approximately 25% of children who fit the diagnostic criteria for ASD at the age of 2 or 3 years subsequently begin to talk and communicate and by age 6 or 7 years blend to varying degrees into the regular school population. Even for this group, social impairments generally continue. For the remaining 75%, most have some improvement with age but continue to require parent, school, and societal support. Excellent reviews of outcomes are provided by Seltzer et al., Howlin et al., Howlin et al., and Farley et al.2629 Some studies indicate that fewer than 5% of children with autism completely recover30; however, relaxation of the diagnostic criteria to include less impaired children seems to be increasing that number. A 20-year follow-up of adults between ages 22 and 46 years diagnosed with autism and average or near-average cognitive abilities in the 1980s found that half the individuals functioned quite well and half were employed in full-time or part-time paying jobs; however, only 12% lived independently and 56% lived with their parents.29 Development of programs aimed at optimizing the transition to adulthood has recently become a major aim, as children diagnosed in the 1990s begin to age out of pediatric services.


Autism is defined completely on the basis of its three core behavioral symptoms: impairment in social interactions, communication, and the propensity for repetitive behaviors. Impairment in social interaction isolates individuals with autism from those around them. Children with classic autism are unable to “read” other people, ignoring them and often strenuously avoiding eye contact. Typically, they do not comfort others or seek comfort and do not share interests with others, such as bringing toys or pictures to their parents. Rather, they use their parents as objects and may climb on them to get to a desired object, pull the parent by the hand, or place the parent's hand on the object, as if the child were using a tool. In clinic, the child who is content to turn pages of a magazine or spin the wheels of a car may become agitated when a simple examination is attempted. The lack of functional or spontaneous make-believe play is characteristic. Toys are lined up, sorted, twirled, or hurled but are not used for imaginative games or imitation of day-to-day activities, such as feeding the baby or washing the dishes. When play emerges later, it is stylized and not spontaneous. Children with autism fail to develop friendships with peers and siblings. In school, they often stand and watch other children from a distance. Some children respond to social overtures but take little social initiative, whereas others seek interaction but have little sense of how to proceed toward normal friendships.

Reciprocal communication, through speech, gestures, or facial expressions, is impaired. Characteristically, young children fail to use eye gaze or pointing to communicate and direct their parent's attention. Early language is limited and when present is characterized by substantially reduced rates of social interaction and establishing joint attention but with more typical rates of requesting. Deficits in pragmatic skills are present throughout life and affect both language and social interaction. The young child seems unable to grasp the concept that speech can be used to name objects, to request a toy, or to engage others. In contrast to the child with nonspecific mental retardation or a primary developmental language disorder who usually has better receptive than expressive language, the child with autism has impaired receptive language. When children with autism learn to talk, they display stereotypic speech that may involve echolalia, pronoun reversal, and unusual inflections and intonations. Unlike typically developing children who begin talking using one-word utterances, children with autism may begin talking in “chunks” composed of commercials, movies, or others' speech. These chunks often convey idiosyncratic meanings, and the child with autism has no understanding of the conventional meaning of the individual words. Pragmatic difficulties including difficulties sustaining a conversation, turn taking, and allowing the conversational partners to introduce their topics, usually continue despite improvement in expressive speech.22

Repetitive and stereotypic behaviors can be noted during the first few months. Infants may stare or rock. Toddlers may have motor “stereotypies” such as movements of fingers, twirling strings, flicking pages of books, or licking. Repetitive whole body movements may include spinning and running back and forth. The repetitive behaviors often have a visual component such as holding the fingers to the side of the face and watching them with a sideways glance. Sometimes the movements become more complex with an individualized sequence of patting, rubbing, or twirling. These stereotypies may last for hours. Although the cause of the repetitive movements is unclear, they seem to have a calming effect and may, especially in the older child, surface in times of stress. This repetitiveness is reflected in a rigid need for sameness in daily routines. Children with autism can develop elaborate rituals in which the order of events, the exact words, and the arrangement of objects must be followed. Failure of parents/caretakers to follow the prescribed order of events results in inconsolable outbursts.

Children with autism also are prone to display a number of symptoms and behaviors that, though not diagnostic, may negatively impact daily living and health. Commonly in the second year of life, children develop meltdowns, aggressive and sometimes self-injurious behaviors brought on by some change in routine, an offending touch, being asked to do something they do not want to do, or for no apparent reason. Extreme hypersensitivity to certain sounds such as the vacuum cleaner may cause great discomfort, causing the child to hold his hands over his ears. The feel of certain clothes or of being touched may be unbearable; conversely, truly painful stimuli, such as a burn or laceration, are ignored. Odd behaviors around foods and their presentation, such as accepting a limited number of foods or only eating french fries that come from McDonalds® occur commonly and have a negative impact on nutrition. Being “in their own world” often leads to a total disregard for danger that results in a high risk of early death, most commonly from drowning.


The behavioral criteria listed in the 1994 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th edition, (DSM-IV)31 remain the standard for making an autism diagnosis in the United States. The 2000 update DSM-IV-TR made some changes in the accompanying text but did not change the diagnostic criteria.32 Currently, three subgroups (autistic disorder [AD], Asperger syndrome [AS], and PDD-not otherwise specified [PDD-NOS]) are recognized. Initially, Rett syndrome, OMIM# 312750, and childhood disintegrative disorder were included as PDDs. Discovery of MECP2 mutations as the cause of Rett syndrome, uncertainty about the nosology of childhood disintegrative disorder, plus a growing understanding of the continuity within the autism diagnoses led to adoption of the term ASDs as the favored umbrella designation for AD, AS, and PDD-NOS.33 It is expected that the DSM-5, due out in 2012 will further simplify the nosology by combining the three subtypes into ASD, with a variety of modifiers such as the degree of mental impairment, neurologic symptoms and, when available, etiology.34

To diagnose autistic disorder, i.e. classical autism, one must precisely enumerate the autism symptoms and their age of occurrence using either the DSM-IV criteria or a number of symptom checklists, structured parent interviews, or observation measures, all of which are based on the DSM-IV Diagnostic Criteria Autistic Disorder.3537 The DSM-IV criteria for AD listed in Table 1 are probably the easiest to use.

Table 1: DSM-IV diagnostic criteria for autistic disorder

Asperger syndrome (AS)3,38 is distinguished from AD by relatively normal language development including timing, grammar, and vocabulary (Section B) but requires all other DSM-IV diagnostic criteria. Individuals with AS are generally loners, are uncomfortable in groups, are unable to empathize with others, maintain a sameness in routine, follow strict rules, and have an encompassing preoccupation with one domain, such as the weather or computers. They generally do not chat and follow a literal interpretation of speech with poor understanding of idioms or jokes. Speech may be pedantic or repetitive with odd intonations. Intelligence quotient (IQ) must be within the normal range to qualify for the diagnosis. Clumsiness is common. Whether AS is the expression of the high end of the autism spectrum or is a discrete genetic entity is unclear.

Although commonly used, the AS diagnosis is problematic with poor concordance between the various diagnostic instruments.39 The Autism Spectrum Screening Questionnaire,40 the Asperger Syndrome Diagnostic Interview,41 the Australian Scale for Asperger's Syndrome,42 and the Childhood Asperger Syndrome Test43 are also available. It is expected that the DSM-5 will drop the term AS, which is a concern to many people who identify strongly with the AS diagnosis and do not want to be lumped diagnostically into a general ASD category.

PDD-NOS is applied to children with autistic symptoms who do not meet full criteria in all three diagnostic domains. This heterogeneous group includes children with milder symptoms in all three diagnostic categories (A, B, and C) and those meeting full criteria for autism in two of the three domains. Sometimes PDD-NOS is used as an initial or tentative diagnosis for younger children or before diagnostic evaluations are completed. Its rather pejorative connotation makes it unpopular with families and many physicians.

An additional ASD designation, with no official standing, is broader autism phenotype that may be used to designate siblings or other family members with some autism symptoms.4446 This terminology was originally adopted by researchers to classify family members considered more likely to carry mutations in putative autism genes. The designation is of little use clinically but does reflect the growing awareness of the broad phenotypic spectrum of ASDs.

A number of diagnostic checklists are commonly used in clinics and schools, including the Childhood Autism Rating Scale (CARS)47 that consists of 15 questions scored by the parent and the tester. It is a reliable, well-verified measure that is relatively fast and easy to administer and, thus, is most often used. A score of 30–35 indicates mild autism and 36 or higher moderate-tosevere autism. Two others are the Aberrant Behavior Checklist (ABC)48 and the Gilliam Autism Rating Scale (GARS).49

In North America, research criteria for the diagnosis of autism depend primarily on the Autism Diagnostic Interview-Revised,36 which is a detailed parent interview, and the somewhat shorter Autism Diagnostic Observation Schedule (ADOS).37 Both scales follow the DSM-IV criteria and were developed in an attempt to sort autism by its behavioral symptoms to permit identification of homogeneous populations. These scales are not widely used in clinical practice because of the time and expense to administer, although the shorter ADOS is becoming more widely used outside of research settings.

Universal autism screening by primary health care providers is recommended starting at a year of age and repeated through 3 years of age. The Checklist for Autism in Toddlers-Modified50 is the most commonly used screening tool. This 23-item checklist, designed for primary care providers to identify at-risk toddlers at the 18-month visit, can be filled out by parents in the waiting room and is available in Spanish and English.35 The Infant/Toddler Checklist from the Communication and Symbolic Behavior Scales Developmental Profile51 is recommended by the American Academy of Pediatrics to identify at-risk children younger than 18 months.52 A positive score on one of these tools is not diagnostic for an ASD but prompts referral to a diagnostic clinic. The push for universal screening comes from multiple research studies which have shown that early intensive educational, language, and behavioral therapy are strong indicators of better outcomes.5355 Also, a number of states including Missouri56 and California35 have developed diagnostic and screening guidelines that are available online or in print free of charge.


Specific neurologic and medical symptoms occur commonly in children with autism, often with profound effects on quality of life for families and long-term outcomes. Seizures develop in approximately 25% of children with autism, and the rate of electroencephalographic abnormalities is increased even when there is no history of seizures.57,58 Although individuals with autism plus seizures are more apt to have moderate to severe mental retardation, motor deficits, and poorer adaptive, behavioral, and social outcomes,59,60 seizures by themselves are not a sensitive outcome predictor. Another particularly disruptive problem is insomnia and abnormal sleep patterns which are reported in approximately 60% of children with autism; this is similar to that reported in other neurologically based syndromes but falls outside the range for typically developing children.61 Although most children with autism develop early motor milestones on time, a number of specific motor impairments including prolonged toe walking, hypotonia, general clumsiness, poor hand writing, and inability to ride a two wheel bicycle are commonly seen. As a group, motor difficulties have not been adequately studied; however, it seems that these symptoms are relatively discrete and not directly correlated with general neurologic disability or IQ. Clumsiness, for instance, is a common characteristic of AS.62 Gastrointestinal symptoms, including constipation, diarrhea, bloating, belching, abdominal pain, reflux, vomiting, and flatulence are reported in approximately 45% of children with autism. A recent consensus report and review indicate that the frequency and character of the gastrointestinal problems are not qualitatively different from what is seen in typically developing children and respond to appropriate medical management.63 Obesity is a common complication of unknown cause. Medication side effects, inactive lifestyle, and difficulty withholding food from children with aggression may be implicated. A recently recognized complication that may develop in as many as 15% of young adults with autism is a catatonia syndrome characterized by a marked deterioration in movement with slowness and freezing in mid movement, vocalizations, and regression of self-care skills.64

The Autism Treatment Network (ATN)65 is a network of treatment and research centers dedicated to improving medical care for children and adolescents with autism by establishing standards of clinical care based on research and shared clinical practice. Analysis of data provided by the ATN registry is providing important information on the frequency and character of medical problems in children with autism and is developing autism-specific diagnosis and treatment algorithms with the goal of enhancing overall well being for children with autism.


Clarifying the “genetics” of autism has proven more challenging than anticipated in the early 1990s, when it was assumed that amassing a DNA collection from approximately 300 autism families and performing genome-wide single nucleotide polymorphism-based association studies would quickly reveal the genes that predispose children to develop autism. Unfortunately, this was not the case; the major genome-wide and candidate gene association studies, which are used to test for common variants contributing to risk, did not identify consistent genomic areas of interest.66 Although, with the recent availability of large DNA repositories and less expensive genotyping, some independently replicated findings from genome-wide association studies are beginning to appear.67,68 The greatest progress toward identifying genetic causes of autism has come from identifying known genetic mutations and disorders that can predispose to development of autism. Using standard medical genetic evaluation techniques, a genetic cause can be identified in 20–25% of children on the autism spectrum. This number has increased with the use of array comparative genomic hybridization (aCGH) also called chromosomal microarrays (CMAs). A small number of cases can be traced to specific teratogenic exposures.69 For the remaining 75–80%, the causes remain unknown. All these percentages are approximate as there is a significant bias of ascertainment, based on the initial referral. Medical Genetics clinics find the highest percentage of identifiable disorders, whereas dedicated autism clinics find the lowest.7,70 This can be explained by the fact that children with autism and significant dysmorphology are more apt to have an identifiable genetic etiology and are more apt to be referred to a medical genetics clinic.

Identified genetic causes of autism can be classified as the cytogenetically visible chromosomal abnormalities (5%), copy number variants (CNVs) (i.e., submicroscopic deletions and duplications) (10–20%), and single-gene disorders (5%).


Cytogenetic abnormalities visible with high-resolution karyotype analysis are found in approximately 5% of children with ASD. Another 3–5% has identifiable chromosomal abnormalities using fluorescence in situ hybridization (FISH) techniques. As expected, unbalanced chromosome abnormalities are found predominantly in children with autism who are dysmorphic.70,71 Cytogenetic abnormalities have been identified on almost every chromosome, although only a few occur with a frequency suggesting the location of a specific autism gene.7274 A curated database of chromosome abnormalities reported in individuals with autism is available at

Maternally derived 15q duplications of the imprinted Prader Willi/Angelman region are the most commonly observed chromosome abnormalities in autism, detected in 1–3%. Cytogenetically visible duplications most often take the form of a de novo supernumerary isodicentric 15q chromosome but can occasionally result from segregation of a maternal chromosome translocation. Identification of interstitial 15q duplications usually requires interphase FISH or aCGH. Similar to the deletions found in most cases of Angelman, OMIM# 105830, and Prader-Willi syndrome, OMIM# 176270, these duplications seem to be mediated by unequal homologous recombination involving low copy repeats (LCR) that are clustered in the region.76 The maternally derived15q11-q13 interstitial duplication is a highly penetrant cause of autism, and the phenotype correlates with the number of 15q copies. A maternal duplication of 15q, resulting in trisomy for that region, causes subtle effects on the physical phenotype, whereas children with four copies of 15q including those with a supernumerary isodicentric 15 are typically more impaired and may exhibit hypotonia, seizures, microcephaly, and severe developmental delay.7779 The paternally derived duplication has little or no phenotypic effect, indicating genomic imprinting of this region.79

Children with Down syndrome, OMIM# 190685, and 45,X Turner syndrome, OMIM# 300082, have autism more often than expected. In one Down syndrome study, the incidence of autism was 7%.80 There are also an excess of girls with Turner syndrome who fit autism diagnostic criteria.81 The explanation for the Down syndrome association is unclear as the social phenotypes of the two disorders are dissimilar. Girls and women with Turner syndrome, on the other hand, generally have poorer social cognition skills.82 Although autism has been reported in other sex chromosome disorders (47,XXX, 47,XXY, and 47,XYY), there does not seem to be a significant association.

aCGH/CMA is rapidly replacing high-resolution chromosomes as the initial test of choice to evaluate children with autism. CGH arrays have identified clinically relevant de novo genomic imbalances in 7–20% of individuals with autism of unknown cause.75,8389 As expected, the yield is higher in those with “syndromic” autism.

  • Using a 1 Mb genome-wide array, Jacquemont et al.71 identified clinically relevant CNVs in 27.5% (8/29) of individuals with autism and dysmorphology, who previously had a normal karyotype as determined by routine cytogenetic studies.

  • Sebat et al.83 found, using an oligonucleotide array, de novo copy number changes in 10% of children from simplex families (i.e., autism in a single family member) and 2% from multiplex families (i.e., autism in multiple family members) compared with 1% in controls.

  • Using a dense genome-wide single nucleotide polymorphism array, Marshall et al.89 found unbalanced CNVs in 44% of 427 unrelated families with autism that were not present in control families. Many of these CNVs were inherited, and only 7% were de novo in persons with autism of unknown cause.

  • A whole-genome CNV study using 550,000 single nucleotide polymorphism markers on a cohort of 859 individuals with ASD and 1,409 healthy children of European ancestry revealed several pathogenic genomic changes in genes encoding neuronal cell-adhesion molecules (NRXN1, CNTN4, NLGN1, and ASTN2) and in genes involved in the ubiquitin pathways (UBE3A, PARK2, RFWD2, and FBXO40).90

  • The International Standard Cytogenomic Array Consortium conducted a literature review of 33 studies, including 21,698 patients tested by aCGH and provided an evidencebased summary of clinical cytogenetic testing comparing CMA with G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. They concluded that CMA offers a much higher diagnostic yield (15–20%) for genetic testing of individuals with unexplained developmental delay (DD)/intellectual disability (ID), ASD, or multiple congenital anomalies than a G-banded karyotype (approximately 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications.87

  • A cohort of 933 patients with autism received clinical genetic testing including G-banded karyotype, fragile X testing, and CMA. Karyotype yielded abnormal results in 2.2%. CMA identified deletions or duplication in 18.2%; for 7%, the variants were considered pathogenetically significant.88

The most common autism-related CNVs are the 15q11.2-11.3 duplications, similar to duplications revealed by FISH, and reciprocal 16p11.2 microdeletions and duplications. The 16p11.2 microdeletions and microduplications of approximately 555 kb are located at a hot spot of genomic instability caused by duplicated blocks of DNA, which lead to unequal crossing over during meiosis. The 7q11.23 duplication of the Williams syndrome region is also found.91,92 Taken together, these CNVs seem to confer susceptibility to ASD in up to 1% of patients with ASD.75,86

No consistent physical or behavioral features identify individuals with 16p11.2 CNVs, but clinical data are limited. Fernandez et al.93 reported phenotypic analysis of five autistic probands with 16p11.2 CNVs (three deletions and two duplications). Of these subjects, three probands and two deletion positive mothers were dysmorphic, the rest were not. One dysmorphic male also had a diaphragmatic hernia. Two deletions and one duplication were de novo and the other two inherited. From samples submitted for clinical aCGH analysis, Shinawi et al.94 identified 16p11.2 deletions and duplications in 0.6% and reported detailed molecular and phenotypic characterization for 17 deletions and 10 duplication subjects. Characterization revealed that speech/language delay and cognitive impairment occurred most commonly followed by motor delays, seizures, behavior problems, dysmorphology or congenital anomalies, and autism.94 Patients with the 16p11.2 deletion were more apt to be macrocephalic (P < 0.002) and 20% had autism, whereas 60% of patients with the duplication had microcephaly and attention deficient hyperactivity disorder (ADHD). Two patients had normal cognitive and behavioral phenotypes, one with the deletion and one with the duplication. The authors suggest the autism plus macrocephaly observed in deletion patients and ADHD plus microcephaly in duplication patients may indicate a diametric model for these genomic sister disorders.

A number of other CNVs have been described in a few autism families, and although none seem to be particularly common, they highlight the potential of array-based techniques to point autism researchers toward specific autism genes within the CNVs. For instance, haploinsufficiency of CHRNA7 may be causative for the majority of neurodevelopmental phenotypes identified with the 15q13.3 microdeletion syndrome9599 at the distal end of the Prader Willi syndrome/Angelman region.100 Another example is the identification of de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated individuals with autism and mental retardation.101

There are significant limitations to our current understanding of CNVs as causes of autism. First, penetrance is extremely variable. Both deletions and duplications may be inherited or occur de novo.93,102,103 In addition, unaffected parents and family members may carry the same CNV as the ASD proband. Microdeletions are more likely to be penetrant and associated with nonspecific major or minor dysmorphism than the duplications, although this is not a constant. Second, microdeletions and duplications cannot be lumped together as their phenotypic consequences are generally different. Finally and perhaps most importantly, patients with a spectrum of other neurocognitive phenotypes, including mental retardation/DD, seizures, ADHD, dyslexia, schizophrenia, and bipolar disorder have been described with the same CNVs.104106 This association of many disorders with the same genetic defect indicates that although specific CNVs may predispose to a variety of neurologic disorders, the specifics of the final phenotype will depend on the individual's genetic background.107 These findings support a second hit model to explain the causality of non-syndromic neurodevelopmental disorders including autism, DDs, neuropsychiatric disease, seizures, epilepsy and others.108 In multiplex autism families, Itasara et al.109 found affected probands were significantly enriched for de novo CNVs compared with their unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. Girirajan et al.108 observed that children with developmental delay were more apt to carry both an inherited 16p12 deletions plus a second large (>500 kb) CNV. This supports the disease model in which the presence of 16p12 by itself results in predisposition to disease and when in combination with other risk-conferring variants can explain the variable expressivity and clinical heterogeneity of many genomic disorders. Some consider this a second hit explanation. Future studies that correlate specific CNVs with clinical characteristics, that assess complete family histories, and that discover the responsible genes, their pathways, and effects on brain development will undoubtedly resolve much of the current perplexity. For now, explaining the significance of a CNV can be difficult94,110,111 and generally requires interpretation by a clinical geneticist.


Autism or autistic features are commonly identified in a large number of single-gene disorders. Autism in these cases is often referred to as “syndromic autism.” That terminology, however, is misleading because by definition autism is a syndromic disorder with variable expression and penetrance. A more accurate designation would be “autism of known etiology.”


Approximately 1–3% of children ascertained on the basis of autism diagnosis can be shown to have fragile X syndrome, OMIM# 300624, with expansion of the CGG trinucleotide repeat in the FMR1 gene to full mutation size of 200 or more repeats. Moreover, a considerable number of children being evaluated for autism have been found to have FMR1 premutations (55–200 CGG repeats).72,112116 Farzin et al.114 studied 14 boys with premutations ascertained through an autism clinic and found 71% met ASD diagnostic criteria. In the authors' experience, 10 of 488 (2%) persons ascertained through a dedicated autism clinic had either an FMR1 full mutation or premutation. Of the five children with a full mutation, only one was diagnosed with AD; four did not meet criteria for an ASD diagnosis. For the five premutation carriers, four were diagnosed with AD and one with PDD-NOS. From the other perspective, we know that at least half of children with fragile X syndrome exhibit some autistic behaviors, such as avoidance of eye contact, language delays, repetitive behaviors, sleep disturbances, tantrums, self-injurious behaviors, hyperactivity, impulsiveness, inattention, and sound sensitivities. In one study of 63 males with fragile X syndrome, 30% met criteria for AD and 30% criteria for PDD-NOS.117 There is undoubtedly a major behavioral overlap between fragile X and autism, and these data underscore the importance of performing FMR1 molecular genetic testing in all children being evaluated for an ASD, to optimize diagnostic accuracy and genetic counseling. From a research perspective, this overlap is beginning to enhance our understanding of the underlying molecular/genetic mechanisms of these two disorders. Molecular studies indicate that the FMR1 gene may cause the autism phenotype by two mechanisms, RNA toxicity to the neurons and gene silencing, which affects neuronal connectivity.118120


A particularly intriguing association is autism as a PTEN (phosphatase and tensin homolog) macrocephaly syndrome. The PTEN gene was initially described as a tumor suppressor gene associated with a broad group of disorders referred to as PTEN hamartoma tumor syndrome, which includes Cowden syndrome, OMIM# 158350, Bannayan-Riley-Ruvlacaba syndrome, OMIM# 153480, Proteus syndrome, OMIM# 176920, and Lhermitte-Duclos disease, OMIM# 158350.121123 More recently, heterozygous PTEN gene mutations have been identified in a subset of individuals with autism and macrocephaly,124126 and PTEN haploinsufficiency has been recognized to play a role in brain development, including neuronal survival and synaptic plasticity. How PTEN causes autism is unclear, although an intriguing recent report indicates that the effect may be related to repression of the phosphoinositide 3-kinase pathway. Page et al.127 found that haploinsufficiency for PTEN and the serotonin transporter gene SLC6A4 act synergistically to increase brain size and decrease sociability in a mouse model. As we try to identify autism-associated metabolic pathways, it is intriguing that in addition to PTEN, mutations in other repressors of phosphoinositide 3-kinase pathway have also been associated with ASD, including the tuberous sclerosis complex genes TSC1 and TSC2128 and neurofibromin 1.129

The frequency of PTEN mutations as a cause of ASD is unclear; results from studies of children ascertained through autism and macrocephaly range from 1%125 to 8.3%126 to 17%.124 Both de novo and familial PTEN mutations have been identified in this population. It may be significant that more of the children studied by Buxbaum et al.,125 who found PTEN mutations in 1%, were from multiplex families, whereas the children studied by Butler et al.,124 who found PTEN mutations in 17% were from simplex families.

Children with ASD who are found to have a PTEN mutation generally have extreme macrocephaly ranging from +3.7 to +9.6 SD (average: +5.4 SD).125 In addition, mutation of PTEN is not specific for autism: Varga et al.126 found children with macrocephaly and mental retardation but not autism had a similar chance of having a PTEN mutation. Because PTEN germline mutations are associated with the phenotypically broad PTEN hamartoma tumor syndrome, it is recommended that children with PTEN mutations and their families be evaluated by a medical geneticist for clinical signs of any of the related disorders. Moreover, because these disorders carry a risk of cancer, including cancer of the breast, thyroid, endometrium, and kidney, these individuals need to be involved in a tumor surveillance program.


Rett syndrome is one of the original DSM-IV designated PDDs and the only one for which a specific genetic etiology has been identified.130 Ninety-six percent of individuals with classic Rett syndrome have mutations in the X-linked MECP2 gene.131 Overall, MECP2 mutations have been reported in approximately 1% of children diagnosed with autism.74,131 The phenotype of MECP2-confirmed Rett syndrome overlaps considerably with autism of unknown cause; children with both often have a period of normal development followed by loss of language with stereotypic hand movements. However, Rett syndrome can usually be distinguished clinically based on a decreasing rate of head growth, progressive gait disturbance, and hand wringing in early childhood. Initially, the distinction may be difficult as illustrated by a study of two Rett syndrome databases that found 17.6% (55/313) of girls with MECP2-confirmed Rett syndrome had been given an early diagnosis of autism.132 A retrospective analysis of the phenotype of girls initially diagnosed with autism showed that they had significantly milder, later developing Rett syndrome symptoms and were more likely to remain ambulatory and to retain some functional hand use. They were also more likely to have mutations p.R306C or p.T158M. On the basis of these data, Young et al.132 recommend that all girls diagnosed with autism be monitored carefully for evolving signs of Rett syndrome including deceleration in head growth. This approach seems prudent and more appropriate than doing MECP2 molecular genetic testing in all girls diagnosed with apparently classic autism.

Evidence of variable expression of the protein MECP2 in the brains of individuals with both autism and Rett syndrome and evidence that MECP2 deficiency can reduce expression of the genes UBE3A and GABRB3 implicated in autism indicate some causal relationship between the two disorders.133,134 Intensive study of the role of MECP2 in maintaining neuronal function and evidence of symptom reversal of neuronal symptoms in mice after reactivation of the silenced MECP2 gene is projected to have implications for autism treatment.135


Although 25–50% of mentally retarded individuals with tuberous sclerosis complex (TSC), OMIM# 191100, fulfill autism diagnostic criteria, only 1.1–1.3% of individuals initially diagnosed with ASD has TSC.136139 Early-onset infantile spasms and temporal lobe tubers on magnetic resonance imaging (MRI) examination increase the chance that children with TSC2 mutations will also develop autism.140

In a prospective study of children with TSC evaluated using the ADOS, 66% met criteria for autism or ASD at age 18 months of age, 54% at 24 months of age, 46% at 36 months of age, and 50% at 60 months of age. The children with both TSC and autism were more cognitively impaired than those with TSC only.141

An evaluation for signs of TSC including skin lesions (hypopigmented macules, shagreen patches, and adenoma sebaceum) and a family history consistent with autosomal dominant inheritance of TSC signs (seizures, skin lesions, and mental retardation) are generally sufficient to indicate or rule out the diagnosis of TSC in children with autism. Molecular genetic testing for the two causative genes, TSC1 and TSC2, is clinically available. Recurrence risks for families with a child with autism due to TSC may be significantly higher than for families with autism of unknown cause.


Timothy syndrome, OMIM# 601005, an autosomal dominant disorder of calcium channels caused by a mutation in the CACNA1C gene at 12p13.3 is characterized by severe QT prolongation, syndactyly, cardiac defects, dysmorphic faces, developmental delays, and autistic symptoms.142 Hope et al.143 reported a CACNA1F mutation at Xp11.23 causing congenital stationary night blindness with autism, mental retardation, and seizures in hemizygous males. Subsequently, we evaluated a young boy with congenital stationary night blindness, classic AD, mental retardation, and mild dysmorphology who also has a CACNA1F mutation. In addition, deleterious mutations in CACNA1H were identified in six of 461 individuals with autism and in none of 480 ethnically-matched controls.144 Timothy syndrome, autism with congenital sensory night blindness and mutations in the CACNA1H gene indicate that alterations in ion channel function may produce autism.


This autosomal recessive disorder is characterized by partial or complete agenesis of the cerebellar vermis, seen as the “molar tooth sign” on MRI, abnormal breathing, abnormal eye movement, cognitive impairment, and behavioral problems. A subset of Joubert syndrome, OMIM# 213300, seems related to the AHI1 gene, encoding the “jouberin” protein.145 In one study, 4 of 11 children with Joubert syndrome met diagnostic criteria for an ASD.146 However, Takahashi et al.147 delineated behavioral and genetic differences between autism and Joubert syndrome implying that these are etiologically distinct disorders. In a report of monozygotic (MZ) twins with Joubert syndrome,127 the twin with the more severe cerebellar abnormality had autism, suggesting that some disorders may have the potential to cause the autism phenotype when other brain regions or circuits are affected.


Mitochondrial disorders

Although mitochondrial respiratory chain disorders have only been reported on rare occasions in autism, elevated plasma concentrations of lactate have been noted frequently.148,149 A population-based study of 69 children with autism reported an elevated plasma lactate concentration in 20% (14/69); 11 of the 14 underwent muscle biopsy and five had a deficiency of one or more respiratory chain complexes, most frequently Complexes I, IV, and V, confirming mitochondrial disease.150 Thus 4.5% of 120 children with ASD were determined to have a definite mitochondrial disease. If confirmed, this would be the largest etiologic autism subgroup. Identifying a mitochondrial disorder is more likely in autistic children with atypical features such as hypotonia, fatigue with activity, epilepsy, failure to thrive, intermittent episodes of regression and regression following fever than in children without these findings. Weissman et al.151 analyzed data from 25 persons with a mitochondrial disorder and an initial diagnosis of autism and found they could all be distinguished from autism of unknown cause on the basis of an abnormal neurologic examination and/or an elevated plasma lactate concentration. However, mitochondrial dysfunction has also been reported in persons with ASD without additional neurologic features.152,153 A comprehensive current review by Hass is recommended.154


Comorbidity of ASD and phenylketonuria (PKU), OMIM# 261600, was consistently described in the literature before universal PKU newborn screening in the United States. The autism was usually complicated by the severe mental retardation. A recent systematic study found that none of 62 persons with PKU who were diagnosed and treated early met diagnostic criteria for autism, whereas 5.7% (2/35) of individuals with late diagnosis of PKU fulfilled the diagnostic criteria for ASD.155

Adenylosuccinate lyase deficiency

This rare autosomal disorder of de novo purine synthesis results in the accumulation of succinylpurines in body fluids. In about half of the affected individuals, the variable clinical manifestations include developmental delay, seizures, and autism symptoms including failure to make eye contact, repetitive behavior, agitation, temper tantrums, and aggression.156 In one study, 1 of 420 children with PDD was found to have adenylosuccinate lyase deficiency, OMIM# 103050.157

Creatine deficiency syndromes

Three inborn errors of creatine metabolism have been described with autism symptoms. Two are creatine biosynthetic disorders, guanidinoacetate methyltransferase deficiency, OMIM# 601240, and l-arginine:glycine amidinotransferase deficiency, OMIM# 602360, and the third is the X-linked SLC6A8 creatine transporter deficiency, OMIM# 300036. Mental retardation and seizures are common to all three. Approximately 80% of individuals with guanidinoacetate methyltransferase deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; approximately 45% have pyramidal/extrapyramidal findings. Onset is between 3 months and 3 years of age. Only five individuals with l-arginine:glycine amidinotransferase deficiency have been reported. The phenotype of SLC6A8 deficiency in affected males ranges from mild mental retardation and speech delay to severe mental retardation, seizures, and behavioral disorder, with onset between ages 2 and 66 years. Learning and behavior problems have been reported in approximately 50% of the SLC6A8 heterozygous female. Recent sequencing of the SLC6A8 gene in 100 males with ASD did not detect deleterious mutations,158 suggesting the prevalence of creatine deficiency syndromes in ASD is low.

Smith-Lemli-Opitz syndrome

This autosomal recessive multiple congenital anomaly and mental retardation syndrome, caused by a deficiency of 7-dehydrocholesterol reductase, can be associated with autism and other behavioral characteristics such as repeated self-injury, sensory hyper reactivity, temperature dysregulation, and sleep disturbance.159,160 Rates of autistic behavior reported in individuals with Smith-Lemli-Opitz syndrome, OMIM# 270400, range from 50 to 86%.161 One study found that three fourths of the children with Smith-Lemli-Opitz syndrome fit criteria for an ASD; half were diagnosed with AD and half with PDD-NOS.162 No correlation was found between the abnormal metabolites and the presence or severity of autistic symptoms.

Other single-gene disorders

Autism or autistic features have been reported in children with many other single-gene disorders. Most are associated with severe mental retardation and significant dysmorphology, and the children are rarely referred with an initial question of autism. For common disorders such as neurofibromatosis 1, it is unclear whether this is a chance occurrence of two common childhood disorders or indicates a true association, perhaps related to macrocephaly common to both disorders. The list includes the following:

  • Cohen syndrome, OMIM# 216550163

  • Cole Hughes macrocephaly syndrome, OMIM# 605309164

  • San Filippo syndrome, OMIM# 252900165

  • Cornelia de Lange syndrome, OMIM# 122470166

  • Angelman syndrome167,168

  • Williams syndrome, OMIM# 194050169 and its reciprocal 7 q11.23 microduplication syndrome91,92

  • 17p11.2p11.2 duplication syndrome, OMIM# 610883170

  • 22q11.1 deletion syndrome171

  • WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation), OMIM# 194072172

  • Duchenne muscular dystrophy, OMIM# 310200173

  • Sotos syndrome, OMIM# 117550174

  • Neurofibromatosis 1, OMIM# 162200136,175,176


Moebius syndrome or sequence

Defined by unilateral or bilateral palsy of the sixth and seventh cranial nerves, Moebius syndrome, OMIM# 157900, is characterized by facial paralysis with inability to smile and fully abduct the eyes. It is often associated with abnormal tearing, seizures, hearing loss, and limb anomalies. Approximately 30% of children with Moebius syndrome develop ASD.177179 A recent study confirmed the observations of Johansson et al.177 that ASD occurs more frequently in individuals with Moebius syndrome with concurrent mental retardation.180 Presumably caused by an early disruption of embryonic blood supply leading to brainstem disruption, Moebius syndrome has been compared with thalidomide embryopathy that also damages the sixth and seventh cranial nerves and causes autism.

Landau-Kleffner syndrome

A small subset of children with ASD and late regression has Landau-Kleffner syndrome, OMIM# 245570. These children develop gradual or sudden isolated language regression associated with seizures (epileptic aphasia) and/or severe electroencephalogram (EEG) abnormality in deep sleep.181 In general, both the seizures and language impairment improve with normalization of EEG abnormalities.58


The search for environmental causes of autism has been motivated by the increased autism prevalence over the last 20 years and the incomplete concordance for autism in MZ twins.

In utero exposures, including valproic acid, thalidomide, and misoprostol (an abortifactant commonly used in South America) are recognized causes of autism. The Liverpool and Manchester Neurodevelopment Group recently reported a long-term study of 632 children exposed to antiepileptic drugs during gestation and found that children exposed to valproate in utero were seven times more likely to develop autism than those not exposed to antiepileptic drugs. None of the families had a known family history of autism. They recommend that women taking valproate be informed of the risk for autism in children exposed during gestation.182

Other factors that have been considered as causes of autism include expanded use of assisted reproductive technologies183 and tocolytic drugs such terbutaline.184

Childhood immunizations given around the time regressive-onset autism is recognized have been a major focus of concern, especially from autism parent groups. Thimerosal, the organic mercury-based preservative used in a number of childhood vaccines in the United States up until 2001 and the measles-mumps-rubella vaccine, which never contained mercury, have been the major targets. Although parental concern is still significant, multiple studies and lines of scientific evidence have identified no support for a relationship between immunizations and autism.18,185188 The original studies by Wakefield et al.189,190 suggesting an association between immunizations and autism have been disproved, the work was retracted by The Lancet.191 In 2010 the British General Medical Council revoked Mr. Wakefield's license to practice medicine. One of the tragedies resulting from fear of an autism epidemic was the decreased use of childhood immunizations leading to outbreaks of measles and childhood deaths.192,193


In addition to clinically identifying known genetic disorders which may predispose to the development of autism, intense efforts have been directed to identifying genes that specifically cause or increase the risk of developing autism. The methods used include both large genome-wide association studies and investigation of candidate genes. The Genetic Association Database194 provides online access to human genetic association studies performed on autism and other complex disorders. Authoritative reviews of the current status of candidate genes and loci are available.195204 SFARIGENE is a new web-based searchable list of candidate genes associated with ASD.204 The candidate genes are richly annotated for their relevance to autism, along with an in-depth, up-to-date view of their molecular function extracted from the current scientific literature.

Table 2 that lists known and putative autism genes is unquestionably incomplete, as new candidate genes are being reported at an unprecedented rate. The genes are organized by pathogenesis to highlight the progress made in the functional assessment of autism candidate genes and pathways. Some genes are included because of their compelling initial descriptions that still await confirmation.

Table 2: Known and putative autism genes (organized by pathogenesis)

A number of these genes are becoming clinically relevant. Of particular recent interest are the synaptic cell adhesion and associated molecules, including neurexin 1, neuroligin 3 and 4, and SHANK3, which implicate glutamatergic synapse abnormalities in ASDs. Mutations in the X-linked neuroligin-3 (NLGN3) and neuroligin-4 (NLGN4X and NLGN4Y) genes196,205 have been identified in brothers with autism.67,206 Laumonnier et al.207 identified a two base-pair deletion in NLGN4 in 12 affected members of a French family with X-linked mental retardation, some of whom were also autistic. Jamain et al.206 identified a C-to-T transition in the NLGN3 gene, in two brothers, one with autism and the other with AS. The mutation was inherited from the mother and was absent in 200 controls. It should be noted that a number of studies failed to find mutations in either NLGN3 or NLGN4 in probands with autism,74 and these mutations have been associated with other psychiatric disorders and language disabilities. Individuals with ASD and mutations in NLGN4 and NLGN3 have typically been nondysmorphic and some have lost of social and verbal milestones at the onset of disease. Molecular genetic testing of NLGN4 and NLGN3 should be considered in families with suspected X-linked inheritance of autism.

The SHANK3 gene, which codes for a synaptic protein that binds directly to neuroligins, seems crucial for the development of language and social cognition. SHANK3 mutations and small cytogenetic rearrangements have been implicated with an ASD phenotype.208,209 In addition, SHANK3 mutations have been found in a variety of disorders including ADHD and language deficits, as well as in unaffected family members, suggesting they may cause disease by acting synergistically with other susceptibility genes. Deletion analysis is clinically available by aCGH.


Initially, multifactorial inheritance was assumed to account for autism's heritability, based on the overall 4:1 male-to-female sex ratio and 4% recurrence risk, both of which are similar to what is found in classical multifactorial disorders such as pyloric stenosis and cleft lip and palate.41,210 However, family studies indicate that autism does not fit the multifactorial threshold model, which predicts that the more frequently affected sex has a lower recurrence risk, and that the less often affected sex is more severely affected. Pickles et al.211 found that the proportion of relatives with mild autism phenotypes was not increased when the proband was female (less frequent sex). In twin studies, Constantino and Todd212 found no evidence for the existence of sex-specific genetic influences and concluded that the lower prevalence (and severity) of autistic traits in girls seem to arise from discrepant phenotypic manifestations of genetic and environmental influences that are common to both sexes. In studies limited to children with essential autism, Miles et al.213 also found that the risk of developing autism in subsequent sibs did not correlate with the sex of the proband. Sibs of male and female probands had an equal chance of developing autism. Both the risk of developing autism and the severity correlated with the gender of the subsequent sib. Females (less frequent sex) were less likely to develop autism, and those who did had less severe symptoms. This indicates that females are in some way protected from developing autism.

This lack of fit to the classic multifactorial threshold model, however, does not eliminate the likelihood that there are many genes and many genetic pathways involved in autism. Rather, it implies that autism is a heterogeneous disorder and that difficulty recognizing heterogeneity within a broad behavioral phenotype has been a major impediment to understanding the genetics of the disorder. For the geneticist, identifying biologically discrete features or phenotypes, which occur in only a portion of individuals with the general diagnosis, is a crucial first step in delineating discrete disorders. However, because autism is a behavioral disorder with few unique physical and laboratory features, this has proven much more difficult than for the prototypic genetic disorders.214,215

There is an emphasis on the identification of phenotypic features (biomarkers or endophenotypes) to facilitate the recognition of subgroups that will enable prediction of outcomes, recurrence risks, and treatment choices.69,216 For autism, the most informative broad separation has been the separation of “complex” from “essential” autism.70 Complex autism is defined by the presence of generalized dysmorphology and/or microcephaly, features that indicate some alteration of early morphogenesis. Approximately 20–30% of children ascertained on the basis of an autism diagnosis have complex autism. Complex autism is associated with a poorer prognosis, a lower male-to-female ratio, and a lower sibling recurrence risk than essential autism. Approximately 25% of children with complex autism can be diagnosed with an autism associated syndrome or chromosome disorder using currently available diagnostic tests.70 Children with essential autism, defined by absence of generalized dysmorphology and/or microcephaly are more likely to be male, have a higher sibling recurrence risk, and have a greater family history of autism and autism-related disorders such as alcoholism and depression than children with complex autism. Testing is less apt to discover a syndrome or chromosome diagnosis. Differences in the sex ratio, recurrence risk, and family history of autism and related disorders provide the best evidence that the separation of complex from essential autism is etiologically valid. Individuals with essential autism are twice as likely to be male (6.5:1 vs. 3.2:1), are more than twice as likely to have a family history of autism (20% vs. 9%), and have a sib recurrence risk of 4–6% compared with no recurrences in the 46 families of children with complex autism. Also, sibs of children with essential autism are twice as likely to have mild autistic traits as those with complex autism (12% vs. 6%).

The distinction between complex and essential autism represents the first pass at dissecting the etiologic heterogeneity within the autism diagnosis. Although each group remains heterogeneous, the functional and genetic differences indicate that essential autism and complex autism are inherently different. Complex autism captures the subgroup of children whose physical phenotype indicates a different embryological process. Analysis of specific morphologic abnormalities is expected to direct research toward specific developmental pathways. And removing complex autism probands from populations used for linkage and sib pair analyses is expected to improve the power of the analyses.

Table 3 lists additional phenotypic variables that may help delineate discrete autism subgroups. In many ways, the transition of autism from an inclusive behaviorally defined disorder to an etiological-based nosology mirrors the history of mental retardation, which, beginning in the 1960s, was divided into subgroups based on phenotypic differences. A number of current autism heritability theories follow this reasoning. Geschwind and Levitt218 proposed that there are significant numbers of highly penetrant autism-causing genes that occur in small groups of families. The hope is that by identifying these rare alleles, we can elucidate their pathways and pathogenetic mechanisms and apply that information to the analysis of autism generally. An extension of this proposal posits that genetically there are two classes of autism; the most common of which is genetic but not heritable.219 Those cases are due to new mutations, a hypothesis suggested by reports of increased parental age in autism220,221 and the identification of de novo CNVs. The expectation is that studies of simplex families will identify a host of de novo genetic changes. A second class of mutations is hypothesized to be familial and account for most sibling recurrences. One analysis of familial cases from the Autism Genetic Resource Exchange data set suggested that the heritable genes were often carried by the mother who although unaffected had affected sons.222 They concluded that this mechanism would account both for the high male prevalence and the families with multiple affected children. However, studies by Constantino and Todd212,223 suggest that this explanation of recurrence is unlikely. Constantino and Todd223 demonstrated that in most families, autistic traits as measured by Social Responsiveness Scale (SRS) are continuously distributed and moderately to highly heritable. First-degree relatives of autism probands including clinically unaffected siblings, mothers, and fathers have SRS scores midway between the affected child and the norm in the general population. In addition, 7 to 15-year-old twins selected only on the basis of their twin status were found to have highly correlated SRS scores; significantly higher correlations were found in MZ than dizygotic twins.212 The Constantino data are consistent with family history studies, which reveal that family members of autistic probands have an increased likelihood of exhibiting autistic symptoms with a wide range of severity, often below the threshold for a diagnosis of an ASD. Social aloofness, language delays, repetitive or stereotypic activities or interests, and psychiatric symptoms and disorders are reported more often in clinically unaffected siblings, parents, and second-degree relatives.44,136,211,224,225 This suggests that for most cases, autism is both genetic and heritable with many “small-effect” inherited changes with as-yet-undetermined interactions.

Table 3: Phenotypic variables that may define discrete autism (ASD) subgroups


In addition to a behavioral assessment to establish the autism diagnosis and cognitive testing to help establish the best educational programs, the evaluation of all individuals with autism should include a medical evaluation to identify medical issues that affect the development and behavior of nonverbal children and a clinical genetics evaluation to elucidate diagnostic possibilities. Recent reports from the American Academy of Pediatrics,52 the American College of Medical Genetics,7 and in Gene Reviews69 provide practical approaches to the evaluation of children with ASD. The ATN registry is currently collecting data on the sensitivity and specificity of specific diagnostic tests.65 In the mean time, the medical geneticist should approach the evaluation of the child with autism similar to that of any child presenting for diagnostic evaluation, i.e., beginning with a records review, a careful family history, the clinical examination, and consideration of the differential diagnosis.


A three-generation pedigree should be analyzed with attention to behavioral and neurologic diagnoses. Family studies reveal significant clustering of neuropsychiatric disorders including depression, manic depression, obsessive compulsive disorder, social phobia, anxiety disorders, alcoholism, substance abuse, seizures, and motor tics, in addition to ASD phenotypes in relatives of autism probands.44,224226 Family histories of alcoholism and other addictive disorders, often not focused on in the medical genetics clinic, should be ascertained. Lobascher et al.227 reported a greater incidence of alcoholism (35%), psychiatric illness (35%), and mental retardation (26%) in the parents of autistic children. DeLong and Dwyer228 reported that 55% of their 51 autism families had a first- or second-degree relative with alcoholism although the overall incidence rate of alcoholism among all 929 first- and second-degree relatives was only 6.5%. In a study of 36 autism families, Smalley et al.229 compared the lifetime rates of psychopathology based on direct SADS-LA interviews of parents and adult siblings of autism probands and found that 47% (17/36) of the autism families had a first-degree relative with substance abuse, including alcoholism, versus none in the 21 control families. In addition, 22% of first-degree relatives reported substance abuse compared with none in the controls (P = 0.002). They also found increased rates of depression (32.3% vs. 11.1%; P = 0.013) and social phobia (20.2% vs. 2.4%; P = 0.016).229 In 2003, we reported pedigree analyses of 167 autism families finding that 39% of autism-ascertained families could be classified as having probable genetic alcoholism, based on either alcoholism in a parent or a cluster of alcoholism in at least one branch of the family.225 The high-alcoholism families had an elevated percentage of affected relatives in all categories, with 17% of mothers, 52% of fathers, 14% of maternal grandmothers, 41% of maternal grandfathers, 21% of paternal grandmothers and 45% of paternal grandfathers reported as alcoholic. The remaining 102 families reported scattered individuals with alcoholism in unrelated branches of the family (<1% of females and <10% males). Evaluation of the autism probands from the high- and low-alcoholism groups differed in two important autism phenotypes, macrocephaly and type of autism onset. Children from the high-alcoholism families were 2.8 times less likely to be macrocephalic (14.7% vs. 40.6%) (P = 0.0006). This significant inverse relationship between high-alcoholism family histories and macrocephaly suggests that whatever genes predispose to both autism and macrocephaly are different and operate independently from gene(s) that predispose to alcoholism and autism. The second difference between the autism probands from high- versus low-alcoholism families was the clinical course of their AD. Children from high-alcoholism families were 1.5 times more apt to present with a regressive onset (52.5% vs. 35.8%) (P = 0.04). The genetic overlap between autism, alcoholism, and other neuropsychiatric disorders indicates that there are autism subgroups that are genetically mediated, highly penetrant, and share biochemical and genetic aberrations.


Height, weight, and occipital-frontal circumference measurements identify microcephaly and growth retardation suggestive of chromosome and monogenic syndromes, whereas macrocephaly, which is present in approximately 35% of children with autism, leads to consideration of the molecularly defined macrocephaly syndromes, especially fragile X and PTEN hamartoma tumor syndrome. A skin examination (including Woods lamp) will detect most cases of tuberous sclerosis complex or neurofibromatosis type 1. The dysmorphology examination that distinguishes between essential and complex autism provides the best information on which to base the diagnostic plan. In addition to the gold standard dysmorphology examination performed by the medical geneticist, a brief Autism Dysmorphology Measure has been developed for use by nondysmorphologists who evaluate children with autism.217 By assessing 12 physical features (height, hair growth patterns, ears, face, nose size, philtrum, mouth and lips, fingers and thumbs, hand size, feet and toes) and use of a scoring algorithm children with generalized dysmorphology can be distinguished from those with essential autism with 81% sensitivity and 99% specificity.217 The great majority of known genetic causes of autism are identified in children with generalized dysmorphology.


At the time of the initial evaluation, it is recommended that children with autism have blood drawn for aCGH and FMR1 molecular genetic testing for both full mutations and premutations. Metabolic evaluation, including quantitative plasma amino acids, urine organic acids, purines, creatine, and guanidinoacetate in urine and serum concentration of lactate, pyruvate, creatine kinase, and uric acid and complete blood count, is of limited benefit for the majority of individuals with autism. However, because diagnosing and treating a metabolic disorder can significantly alter prognosis, a selective and targeted metabolic work up is recommended based on history and physical examination. The evaluation should include a review of the results of the child's newborn screening tests.


The utility of obtaining a routine sleep-deprived EEG and brain MRI is debated. Certainly, clinical signs of seizures or developmental regression should prompt an EEG. It is clear that a significant number of children with autism have EEG abnormalities, and the likelihood of observing an abnormality increases with the duration of the EEG. The brain MRI is indicated when the history and physical examination or neurologic examination suggests a localized lesion, tuberous sclerosis complex, Joubert syndrome, or an early environmental insult. Obtaining an MRI in children with autism generally requires sedation or anesthesia by an anesthesiologist, and it is recommended that centers who routinely evaluate children with autism develop an autism-specific EEG and MRI protocol with attention to decreasing sensory stimulation.


Genetic counseling is best done by a medical geneticist after a careful diagnostic evaluation. For those families where a specific etiology has been identified, the risk of recurrence in siblings generally depends on the etiologic diagnosis. For autism of unknown cause, the sibling risk varies across studies but is generally considered to range from 5 to 10% for autism and 10–15% for milder symptoms, including language, social, and psychiatric disorders.70,230233 For families with two or more affected children, the recurrence risk approaches 35%.234 No recurrence risk data are available for families who have one autistic child plus another child or relative with mild autistic symptoms. Therefore, the amount of weight to put on mild autistic symptoms in siblings, parents, and other relatives when estimating recurrence risk for families is unknown.

Separation of essential and complex autism helps in the estimate of recurrence risks for autism of undetermined cause. In one study, brothers of a proband with essential autism had a 7% risk for autism and an additional 7% risk for milder autism spectrum symptoms; sisters had a 1% risk for autism. Their risk for milder ASD is unknown.69,70 Complex autism, defined by generalized dysmorphology or microcephaly, when no known etiology has been found carries a lower sibling risk. The empiric risks are 1% for autism and an additional 2% for milder autism spectrum symptoms.


The genetics of autism is intriguing partially because we are beginning to understand what controls human behavior. However, for the clinical geneticist who can interpret family, developmental, and medical histories and truly understands penetrance, expressivity, physical variation, and heterogeneity, the study of autism and all its unanswered questions must have immense intellectual appeal. A case in point is the ongoing debate over whether autism, as a common disease, conforms to the common variant (CD/CV) or to the rare variant (CD/RV) hypothesis. The CD/CV hypothesis expects that a few common allelic variants will account for the genetic variance in disease susceptibility; whereas the CN/RV hypothesis posits that numerous rare mutations may cause the disorder, with the most extreme being that each mutation is only found once in the population.234 The recent success in mining autism genes identified from CNVs and from isolated families with rare causes of their autism supports the CD/RV hypothesis, whereas family studies of Constantino and others suggest that there is a role for common variants in the determination of autism-related behaviors. Although it seems clear to the clinical geneticist that both hypotheses must be correct for some autism subgroups, it will take additional research to clarify the underlying genetics, especially for children with essential autism. Designing and interpreting this research will benefit from having more clinical geneticists join research teams and bring their understanding of phenotype analysis, their ability to obtain and interpret family pedigrees and their experience deciphering the nosology of complex phenotypes.


  1. 1.

    National Institute of Mental Health. Autism Spectrum Disorders (Pervasive Developmental Disorders). Available at: . Accessed July 13,2010 ;

  2. 2.

    . Autistic disturbances of affective contact. Nervous Child 1943; 2: 217–250.

  3. 3.

    . Die autistischen psychopathen in kindersalter. Cambridge, Cambridge University Press. 1944;

  4. 4.

    , . Autism. The search for susceptibility genes. Lancet 2001; 358: suppl S3.

  5. 5.

    , , . Autism and Genetics. Arch Gen Psychiatry 1988; 45: 953–961.

  6. 6.

    , , , et al. The UCLA-University of Utah epidemiologic survey of autism: recurrence risk estimates and genetic counseling. Am J Psychiatry 1989; 146: 1032–1036.

  7. 7.

    , . Clinical genetics evaluation in identifying the etiology of autism spectrum disorders. Genet Med 2008; 10: 301–305.

  8. 8.

    . Is there an epidemic of autism?. Pediatrics 2001; 107: 411–412.

  9. 9.

    , , , , , . Autism in 3–6-year-old children in a suburb of Goteborg, Sweden. Autism 1997; 1: 163–173.

  10. 10.

    , , , et al. A screening instrument for autism at 18 months of age: a 6-year follow-up study. J Am Acad Child Adolesc Psychiatry 2000; 39: 694–702.

  11. 11.

    , . Pervasive developmental disorders in preschool children: confirmation of high prevalence. Am J Psychiatry 2005; 162: 1133–1141.

  12. 12.

    Centers for Disease Control and Prevention Prevalence of autism and Brick Township, New Jersey, 1998: community report. Atlanta, GA, Department of Health and Human Services 2000;

  13. 13.

    , , , et al. Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007. Pediatrics 2009; 124: 1395–1403.

  14. 14.

    Centers for Disease Control and Prevention Prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network, United States, 2006. MMWR Morb Mortal Wkly Rep 2009; 58: 1–20.

  15. 15.

    , , . Three reasons not to believe and autism epidemic. Curr Dir Psychol Sci 2005; 14: 55–58.

  16. 16.

    , , , , . Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations. Pediatrics 2006; 118: e139–e150.

  17. 17.

    . Diagnostic substitution and changing autism prevalence. Pediatrics 2006; 117: 1438–1439.

  18. 18.

    . Vaccines and the changing epidemiology of autism. Child Care Health Dev 2006; 32: 511–519.

  19. 19.

    , , , , , . Time trends in reported diagnoses of childhoon neuropsychiatric disorders: a Danish cohort study. Arch Pediatr Adolesc Med 2007; 161: 193–198.

  20. 20.

    , . The rise in autism and the role of age at diagnosis. Epidemiology 2009; 20: 84–90.

  21. 21.

    . Regression in autistic spectrum disorders. Neuropsychol Rev 2008; 18: 305–319.

  22. 22.

    , , . Regression and word loss in autistic spectrum disorders. J Child Psychol Psychiatry 2004; 45: 936–955.

  23. 23.

    , , . Autism in infancy and early childhood. Annu Rev Psychol 2005; 56: 315–336.

  24. 24.

    , . Validation of the phenomenon of autistic regression using home videotapes. Arch Gen Psychiatry 2005; 62: 889–895.

  25. 25.

    , , , et al. A prospective study of the emergence of early behavioral signs of autism. J Am Acad Child Adolesc Psychiatry 2010; 49: 256–266.

  26. 26.

    , , , . Trajectory of development in adolescents and adults with autism. Ment Retard Dev Disabil Res Rev 2004; 10: 234–247.

  27. 27.

    , , , . Adult outcome for children with autism. J Child Psychol Psychiatry 2004; 45: 212–229.

  28. 28.

    , , . Autism and developmental receptive language disorder—a follow-up comparison in early adult life. II: social, behavioural, and psychiatric outcomes. J Child Psychol Psychiatry 2000; 41: 561–578.

  29. 29.

    , , , et al. Twenty-year outcome for individuals with autism and average or near-average cognitive abilities. Autism Res 2009; 2: 109–118.

  30. 30.

    , . The long-term course of autistic disorders: update on follow-up studies. Acta Psychiatr Scand 1998; 97: 99–108.

  31. 31.

    American Psychiatric Association Diagnostic and statistical manual of mental disorders, fourth edition. Washington, DC American Psychiatric Association. 1994;

  32. 32.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders IV-TR. Washington DC: American Psychiatric Association, 2000; Accessed July 13, 2010.

  33. 33.

    National Institute of Mental Health. Autism Spectrum Disorders (Pervasive Developmental Disorders). Available at: . Accessed July 13, 2010;

  34. 34.

    American Psychiatric Association. DSM-V: the future manual, 2010; Available at: . Accessed July 13, 2010.

  35. 35.

    California Department of Developmental Services Autistic spectrum disorders changes in the California caseload an update: 1999–2002. Sacramento, CA, California Health and Human Services Agency 2002;

  36. 36.

    , , . Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994; 24: 659–685.

  37. 37.

    , , , et al. Autism diagnostic observation schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord 1989; 19: 185–212.

  38. 38.

    , Translation and annotation of “Autistic psychopathy in childhood” by Hans Asperger. Frith U Autism and Asperger syndrome. Cambridge, Cambridge University Press 1991; 36–92.

  39. 39.

    , , , . Three diagnostic approaches to Asperger syndrome: implications for research. J Autism Dev Disord 2005; 35: 221–234.

  40. 40.

    , , . A screening questionnaire for Asperger syndrome and other high-functioning autism spectrum disorders in school age children. J Autism Dev Disord 1999; 29: 129–141.

  41. 41.

    , , , . The Asperger Syndrome (and high-functioning autism) Diagnostic Interview (ASDI): a preliminary study of a new structured clinical interview. Autism 2001; 5: 57–66.

  42. 42.

    , . The Australian scale for Asperger's syndrome. Asperger's syndrome: a guide for parents and professionals. London, Jessica Kingsley Publishers 1997;

  43. 43.

    , , , . The CAST (Childhood Asperger Syndrome Test): preliminary development of a UK screen for mainstream primary-school-age children. Autism 2002; 6: 9–31.

  44. 44.

    , . Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families. Am J Psychiatry 1999; 156: 557–563.

  45. 45.

    , , , , , . Personality traits of the relatives of autistic probands [In Process Citation]. Psychol Med 2000; 30: 1411–1424.

  46. 46.

    , , , et al. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet 2001; 69: 463–466.

  47. 47.

    , , . The Childhood Autism Rating Scale (CARS) for diagnostic screening and classification of autism. New York, Irvington 1986;

  48. 48.

    , , , . The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic 1985; 89: 485–491.

  49. 49.

    . Gilliam Autism Rating Scale (GARS). Austin, Texas, Pro Ed 1995;

  50. 50.

    , , , . The Modified Checklist for Autism in Toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders. J Autism Dev Disord 2001; 31: 131–144.

  51. 51.

    , . Communication and Symbolic Behavior Scales Developmental Profile (CSBS DP): first normed edition. Baltimore, MD, Paul H. Brookes 2002;

  52. 52.

    , . Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007; 120: 1183–1215.

  53. 53.

    , , , . Intensive behavioral treatment at school for 4- to 7-year-old children with autism. A 1-year comparison controlled study. Behav Modif 2002; 26: 49–68.

  54. 54.

    . Identifying effective interventions for young children with autism spectrum disorders. J Intellect Disabil Res 2008; 52: 817.

  55. 55.

    , . Evidence-based comprehensive treatments for early autism. J Clin Child Adolesc Psychol 2008; 37: 8–38.

  56. 56.

    Missouri Autism Guidelines Initiative. Autism spectrum disorders: Missouri best practice guidelines for screening diagnosis,and assessment 2010; Available at: . Accessed July 13, 2010.

  57. 57.

    , , , , . Absence of seizures despite high prevalence of epileptiform EEG abnormalities in children with autism monitored in a tertiary care center. Epilepsia 2006; 47: 394–398.

  58. 58.

    , . The role of epilepsy and epileptiform EEGs in autism spectrum disorders. Pediatr Res 2009; 65: 599–606.

  59. 59.

    , . Epilepsy in autism. Lancet Neurol 2002; 1: 352–358.

  60. 60.

    . Autism and epilepsy: a retrospective follow-up study. Brain Dev 2007; 29: 486–490.

  61. 61.

    , , , et al. Sleep behaviors and sleep quality in children with autism spectrum disorders. Sleep 2009; 32: 1566–1578.

  62. 62.

    , , , , , . An examination of movement kinematics in young people with high-functioning autism and Asperger's disorder: further evidence for a motor planning deficit. J Autism Dev Disord 2006; 36: 757–767.

  63. 63.

    , , et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 2010; 125: suppl 1 S1–S18.

  64. 64.

    , , . Catatonia in autism: implications across the life span. Eur Child Adolesc Psychiatry 2008; 17: 327–335.

  65. 65.

    The Autism Treatment Network, 2010; Available at: . Accessed July 13, 2010.

  66. 66.

    , . The genetic basis of complex traits: rare variants or “common gene, common disease”?. Methods Mol Biol 2007; 376: 71–84.

  67. 67.

    , , , et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009; 459: 528–533.

  68. 68.

    , , , et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann Hum Genet 2009; 73: 263–273.

  69. 69.

    , , , . Autism Spectrum Disorders. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Seattle: University of Washington, 2010; Available at . Accessed July 13, 2010.

  70. 70.

    , , , et al. Essential versus complex autism: definition of fundamental prognostic subtypes. Am J Med Genet A 2005; 135: 171–180.

  71. 71.

    , , , et al. Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet 2006; 43: 843–849.

  72. 72.

    . Cytogenetic abnormalities and fragile-X syndrome in Autism Spectrum Disorder. BMC Med Genet 2005; 6: 3.

  73. 73.

    , , , , , . Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry 2006; 11: 1, 18–28.

  74. 74.

    , . Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist. J Med Genet 2009; 46: 1–8.

  75. 75.

    , , , et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008; 82: 477–488.

  76. 76.

    , , , et al. Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15. BMC Genet 2008; 9: 2.

  77. 77.

    , , , et al. Relationship between clinical and genetic features in “inverted duplicated chromosome 15” patients. Pediatr Neurol 2001; 24: 111–116.

  78. 78.

    , , . Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues. Ment Retard Dev Disabil Res Rev 2004; 10: 284–291.

  79. 79.

    , , , . The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiol Dis 2010; 38: 181–191.

  80. 80.

    , , , . Comorbidity of autistic spectrum disorders in children with Down syndrome. Dev Med Child Neurol 1999; 41: 153–158.

  81. 81.

    , . Autism in association with Turner Syndrome: genetic implications for male vulnerability to pervasive developmental disorders. Neurocase 1999; 5: 101–108.

  82. 82.

    . Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism. Pediatr Res 2000; 47: 9–16.

  83. 83.

    , , , et al. Strong association of de novo copy number mutations with autism. Science 2007; 316: 445–449.

  84. 84.

    , , , et al. Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol Psychiatry 2008; 63: 1111–1117.

  85. 85.

    , , , et al. Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 2008; 17: 628–638.

  86. 86.

    , , , et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358: 667–675.

  87. 87.

    , , , et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86: 749–764.

  88. 88.

    , , , et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 2010; 125: e727–e735.

  89. 89.

    , , , et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008; 82: 477–488.

  90. 90.

    , , , et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 2009; 459: 569–573.

  91. 91.

    , , , et al. Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genet Med 2007; 9: 427–441.

  92. 92.

    , , , et al. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet 2009; 52: 94–100.

  93. 93.

    , , , et al. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. J Med Genet 2010; 47: 195–203.

  94. 94.

    , , , et al. Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 2010; 47: 332–341.

  95. 95.

    , , , et al. Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet 2009; 46: 382–388.

  96. 96.

    , , , et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 2009; 46: 242–248.

  97. 97.

    , , , et al. A 15q13.3 microdeletion segregating with autism. Eur J Hum Genet 2009; 17: 687–692.

  98. 98.

    , , , et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 2008; 40: 322–328.

  99. 99.

    , , , et al. A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region. Molecular Autism 2010; 1010: 5.

  100. 100.

    , , , et al. A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nat Genet 2009; 41: 1269–1271.

  101. 101.

    , , , et al. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat Genet 2010; 42: 489–491.

  102. 102.

    , , , , , . The Xp contiguous deletion syndrome and autism. Am J Med Genet A 2009; 149A: 1138–1148.

  103. 103.

    , , , et al. Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 2009; 46: 223–232.

  104. 104.

    , , . Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet 2009; 25: 528–535.

  105. 105.

    . The role of copy number variation in schizophrenia. Expert Rev Neurother 2010; 10: 25–32.

  106. 106.

    , , , et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010; 133: 23–32.

  107. 107.

    , . Phenotypic variability and genetic susceptibility to genomic disorders. Hum Mol Genet 2010; 19: R176–R187.

  108. 108.

    , , , et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 2010; 42: 203–209.

  109. 109.

    , , , et al. De novo rates and selection of large copy number variation. Genome Res 2010; 20: 1469–1481.

  110. 110.

    , , , et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009; 41: 1223–1227.

  111. 111.

    , , , et al. Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. J Neurodev Disord 2010; 2: 26–38.

  112. 112.

    , , , . Autistic spectrum disorder and the fragile X premutation. J Dev Behav Pediatr 2004; 25: 392–398.

  113. 113.

    , , , et al. The emerging fragile X premutation phenotype: evidence from the domain of social cognition. Brain Cogn 2005; 57: 53–60.

  114. 114.

    , , , et al. Autism spectrum disorders and attention deficit/hyperactivity disorder in boys with the fragile X premutation. J Dev Behav Pediatr 2006; 27: S137–S144.

  115. 115.

    , , , et al. Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X. Neurosci Biobehav Rev 2007; 31: 315–326.

  116. 116.

    , , , , . An fMRI study of the prefrontal activity during the performance of a working memory task in premutation carriers of the fragile X mental retardation 1 gene with and without fragile X-associated tremor/ataxia syndrome (FXTAS). J Psychiatr Res 2011; 45: 36–43.

  117. 117.

    , , , et al. Autism profiles of males with fragile X syndrome. Am J Ment Retard 2008; 113: 427–438.

  118. 118.

    , , , , , . CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein. Neuron 2003; 38: 887–898.

  119. 119.

    , , , et al. Long CGG-repeat tracts are toxic to human cells: implications for carriers of fragile X premutation alleles. FEBS Lett 2005; 579: 2702–2708.

  120. 120.

    , , . The fragile X family of disorders: a model for autism and targeted treatments. Curr Pediatric Rev 2008; 4: 40–52.

  121. 121.

    , , , , . Germline PTEN mutation in a family with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet 1998; 80: 399–402.

  122. 122.

    , , , , , . The spectrum and evolution of phenotypic findings in PTEN mutation positive cases of Bannayan-Riley-Ruvalcaba syndrome. J Med Genet 2001; 38: 52–58.

  123. 123.

    , , , , . De novo germline PTEN mutation in a man with Lhermitte-Duclos disease which arose on the paternal chromosome and was transmitted to his child with polydactyly and Wormian bones. J Med Genet 2003; 40: e92.

  124. 124.

    , , , et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 2005; 42: 318–321.

  125. 125.

    , , , et al. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 484–491.

  126. 126.

    , , , , . The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet Med 2009; 11: 111–117.

  127. 127.

    , , , . Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior. Proc Natl Acad Sci U S A 2009; 106: 1989–1994.

  128. 128.

    , , . The genetics of autism. Pediatrics 2004; 113: e472–e486.

  129. 129.

    , , , et al. Association between the neurofi-bromatosis-1 (NF1) locus and autism in the Japanese population. Am J Med Genet B Neuropsychiatr Genet 2004; 131: 43–47.

  130. 130.

    , , , , , . Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23: 185–188.

  131. 131.

    , . MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev 2006; 16: 276–281.

  132. 132.

    , , , et al. The diagnosis of autism in a female: could it be Rett syndrome?. Eur J Pediatr 2008; 167: 661–669.

  133. 133.

    , , , . Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum Mol Genet 2004; 13: 629–639.

  134. 134.

    , , . Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum Mol Genet 2005; 14: 483–492.

  135. 135.

    . The methyl-CpG-binding protein MeCP2 and neurological disease. Biochem Soc Trans 2008; 36: 575–583.

  136. 136.

    , , , . Autism and associated medical disorders in a French epidemiological survey. J Am Acad Child Adolesc Psychiatry 1997; 36: 1561–1569.

  137. 137.

    , , . Autism and tuberous sclerosis complex: prevalence and clinical features. J Autism Dev Disord 1998; 28: 279–285.

  138. 138.

    , , , et al. Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction. Neurology 2001; 57: 1269–1277.

  139. 139.

    , , . The psychopathologies of children and adolescents with tuberous sclerosis complex (TSC): a postal survey of UK families. Eur Child Adolesc Psychiatry 2007; 16: 16–24.

  140. 140.

    . Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis. Ment Retard Dev Disabil Res Rev 2004; 10: 126–131.

  141. 141.

    , , , , . Characterization of autism in young children with tuberous sclerosis complex. J Child Neurol 2008; 23: 520–525.

  142. 142.

    , , , et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004; 119: 19–31.

  143. 143.

    , , , et al. Clinical manifestations of a unique X-linked retinal disorder in a large New Zealand family with a novel mutation in CACNA1F, the gene responsible for CSNB2. Clin Experiment Ophthalmol 2005; 33: 129–136.

  144. 144.

    , , , , , . CACNA1H mutations in autism spectrum disorders. J Biol Chem 2006; 281: 22085–22091.

  145. 145.

    , , , et al. Association of common variants in the Joubert syndrome gene (AHI1) with autism. Hum Mol Genet 2008; 17: 3887–3896.

  146. 146.

    , , , . Autism and autistic behavior in Joubert syndrome. J Child Neurol 1999; 14: 636–641.

  147. 147.

    , , , , , . Joubert syndrome is not a cause of classical autism. Am J Med Genet A 2005; 132: 347–351.

  148. 148.

    . Advances in autism research. Dev Med Child Neurol 2005; 47: 148.

  149. 149.

    , , , et al. Brief report: high frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene. J Autism Dev Disord 2006; 36: 1137–1140.

  150. 150.

    , , , et al. Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol 2005; 47: 185–189.

  151. 151.

    , , , et al. Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS One 2008; 3: e3815.

  152. 152.

    , , , et al. Mitochondrial DNA abnormalities and autistic spectrum disorders. J Pediatr 2004; 144: 81–85.

  153. 153.

    , , . Nuclear and mitochondrial genome defects in autisms. Ann N Y Acad Sci 2009; 1151: 102–132.

  154. 154.

    . Autism and mitochondrial disease. Dev Disabil Res Rev 2010; 16: 144–153.

  155. 155.

    , , , , . Autism and phenylketonuria. J Autism Dev Disord 2003; 33: 201–204.

  156. 156.

    , , . Inborn errors of the purine nucleotide cycle: adenylosuccinase deficiency. J Inherit Metab Dis 1997; 20: 193–202.

  157. 157.

    , , . Autism and adenylosuccinase deficiency. J Am Acad Child Adolesc Psychiatry 2000; 39: 274–275.

  158. 158.

    , , , , . Screening of male patients with autism spectrum disorder for creatine transporter deficiency. Neuropediatrics 2007; 38: 310–312.

  159. 159.

    , , , , , . Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome. Am J Med Genet 2001; 98: 191–200.

  160. 160.

    , , , et al. Abnormalities of cholesterol metabolism in autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 666–668.

  161. 161.

    , , , . Autism and metabolic diseases. J Child Neurol 2008; 23: 307–314.

  162. 162.

    , , , , . The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am J Med Genet A 2006; 140: 1511–1518.

  163. 163.

    , , . Behavioural characteristics and autistic features in individuals with Cohen Syndrome. Eur Child Adolesc Psychiatry 2005; 14: 57–64.

  164. 164.

    , , . Cole-Hughes macrocephaly syndrome and associated autistic manifestations. Am J Med Genet 2000; 94: 149–152.

  165. 165.

    , , , et al. Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 2007; 120: e1255–e1261.

  166. 166.

    , , , . Behavioural phenotype of Cornelia de Lange syndrome: case-control study. Br J Psychiatry 2008; 193: 466–470.

  167. 167.

    , , , et al. Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations. J Med Genet 2006; 43: 512–516.

  168. 168.

    , , , et al. Evaluation of autism traits in Angelman syndrome: a resource to unfold autism genes. Neurogenetics 2007; 8: 169–178.

  169. 169.

    , , , . Socio-communicative deficits in young children with Williams syndrome: performance on the Autism Diagnostic Observation Schedule. Child Neuropsychol 2007; 13: 444–467.

  170. 170.

    , , , et al. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 2007; 80: 633–649.

  171. 171.

    , , , . Autism, ADHD, mental retardation and behavior problems in 100 individuals with 22q11 deletion syndrome. Res Dev Disabil 2009; 30: 763–773.

  172. 172.

    , , , , , . Characterization of 11p14–p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism. Cytogenet Genome Res 2008; 122: 181–187.

  173. 173.

    , , , , . Association of Duchenne muscular dystrophy with autism spectrum disorder. J Child Neurol 2005; 20: 790–795.

  174. 174.

    , , , et al. Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly. BMC Med Genet 2007; 8: 68.

  175. 175.

    , . Etiologic yield of autistic spectrum disorders: a prospective study. Am J Med Genet C Semin Med Genet 2006; 142: 3–7.

  176. 176.

    , . Diagnostic yield in the clinical genetic evaluation of autism spectrum disorders. Genet Med 2006; 8: 549–556.

  177. 177.

    , , , , , . Autistic spectrum disorders in Mobius sequence: a comprehensive study of 25 individuals. Dev Med Child Neurol 2001; 43: 338–345.

  178. 178.

    , , , et al. Mobius sequence–a Swedish multidiscipline study. Eur J Paediatr Neurol 2002; 6: 35–45.

  179. 179.

    , , , , . Autism and Mobius sequence: an exploratory study of children in northeastern Brazil. Arq Neuropsiquiatr 2003; 61: 181–185.

  180. 180.

    , , , , . Autism spectrum disorders in children and adolescents with Moebius sequence. Eur Child Adolesc Psychiatry 2009; 18: 515–519.

  181. 181.

    , , , . Linking autism, regression and Landau-Kleffner syndrome: integrative role of nerve growth factor. Med Hypotheses 2007; 68: 1178–1179.

  182. 182.

    , , , . Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 2008; 71: 1923–1924.

  183. 183.

    , , , , . Matched follow-up study of 5 8-year-old ICSI singletons: child behaviour, parenting stress and child (health-related) quality of life. Hum Reprod 2007; 22: 3098–3107.

  184. 184.

    , , , et al. beta2-adrenergic receptor activation and genetic polymorphisms in autism: data from dizygotic twins. J Child Neurol 2005; 20: 876–884.

  185. 185.

    Institute of Medicine Safety Review Committee , , , . Immunization safety review: measles-mumps-rubella vaccine and autism. The compass series. Washington, DC, National Academy Press 2001;

  186. 186.

    , . MMR vaccine and autism: an update of the scientific evidence. Expert Rev Vaccines 2004; 3: 19–22.

  187. 187.

    Institute of Medicine Immunization safety review: vaccines and autism. Washington, DC, National Academies Press. 2004;

  188. 188.

    , . Continuing increases in autism reported to California's developmental services system: mercury in retrograde. Arch Gen Psychiatry 2008; 65: 19–24.

  189. 189.

    , , , et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children [see comments]. Lancet 1998; 351: 637–641.

  190. 190.

    . MMR vaccination and autism. Lancet 1999; 354: 949–950.

  191. 191.

    . A statement by Dr Simon Murch. Allegations concerning our 1998 study. Lancet 2004; 363: 821–822.

  192. 192.

    , , , , , . Measles outbreaks in a population with declining vaccine uptake. Science 2003; 301: 804.

  193. 193.

    . Autism's false prophets: bad science, risky medicine and the search for a cure. New York, Columbia University Press 2008;

  194. 194.

    Genetic Association Database, 2010; Available at: . Accesssed July 13, 2010.

  195. 195.

    , , , , . Genetics of autistic disorders: review and clinical implications. Eur Child Adolesc Psychiatry 2010; 19: 169–178.

  196. 196.

    . Multiple rare variants in the etiology of autism spectrum disorders. Dialogues Clin Neurosci 2009; 11: 35–43.

  197. 197.

    . Genetics. Insights into the pathogenesis of autism. Science 2008; 321: 208–209.

  198. 198.

    , . Autism genetics: strategies, challenges, and opportunities. Autism Res 2008; 1: 4–17.

  199. 199.

    , , , et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 2008; 321: 218–223.

  200. 200.

    , , , et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007; 39: 319–328.

  201. 201.

    , . The genetics of autism spectrum disorders. Neuromolecular Med 2006; 8: 451–460.

  202. 202.

    , . Recent advances in the genetics of autism. Biol Psychiatry 2007; 61: 429–437.

  203. 203.

    Online Mendelian Inheritance in Man. Baltimore MD: Johns Hopkins Univesity, 1996; Available at: . Accessed July 13, 2010.

  204. 204.

    SFARIGENE, 2010; Available at: . Accessed July 13, 2010.

  205. 205.

    . Neuroligins and neurexins link synaptic function to cognitive disease. Nature 2008; 455: 903–911.

  206. 206.

    , , , et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003; 34: 27–29.

  207. 207.

    , , , et al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet 2004; 74: 552–557.

  208. 208.

    , , , et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 2007; 39: 25–27.

  209. 209.

    , , , et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 2007; 81: 1289–1297.

  210. 210.

    , . Pervasive developmental disorders in preschool children. JAMA 2001; 285: 3093–3099.

  211. 211.

    , , , et al. Variable expression of the autism broader phenotype: findings from extended pedigrees. J Child Psychol Psychiatry 2000; 41: 491–502.

  212. 212.

    , . Autistic traits in the general population: a twin study. Arch Gen Psychiatry 2003; 60: 524–530.

  213. 213.

    , , , . Autism symptoms are less severe in girls with essential autism. Am J Hum Genet Abstract 2004; 129: 89.

  214. 214.

    , , , et al. Subtypes of pervasive developmental disorder: clinical characteristics. Child Neuropsychology 1999; 5: 1–23.

  215. 215.

    . The genetics of autism. Curr Opin Pediatr 2001; 13: 561–565.

  216. 216.

    , . Endophenotype approach to developmental psychopathology: implications for autism research. Behav Genet 2007; 37: 51–60.

  217. 217.

    , , , et al. Development and validation of a measure of dysmorphology: useful for autism subgroup classification. Am J Med Genet A 2008; 146A: 1101–1116.

  218. 218.

    , . Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol 2007; 17: 103–111.

  219. 219.

    . Autism: highly heritable but not inherited. Nat Med 2007; 13: 534–536.

  220. 220.

    , , , , , . Paternal age increases the risk for autism in an Iranian population sample. Mol Autism 2010; 1: 2.

  221. 221.

    , , , et al. Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. Am J Epidemiol 2005; 161: 916–925.

  222. 222.

    , , , et al. A unified genetic theory for sporadic and inherited autism. Proc Natl Acad Sci USA 2007; 104: 12831–12836.

  223. 223.

    , . Genetic structure of reciprocal social behavior. Am J Psychiatry 2000; 157: 2043–2045.

  224. 224.

    , , , . Autism, affective and other psychiatric disorders: patterns of familial aggregation. Psychol Med 1998; 28: 385–395.

  225. 225.

    , , , . Autism families with a high incidence of alcoholism. J Autism Dev Disord 2003; 33: 403–415.

  226. 226.

    , , , , . A family study of autism: cognitive patterns and levels in parents and siblings. J Child Psychol Psychiatry 1997; 38: 667–683.

  227. 227.

    , , . Childhood autism: an investigation of aetiological factors in twenty- five cases. Br J Psychiatry 1970; 117: 525–529.

  228. 228.

    , . Correlation of family history with specific autistic subgroups: Asperger's syndrome and bipolar affective disease. J Autism Dev Disord 1988; 18: 593–600.

  229. 229.

    , , . Autism, affective disorders, and social phobia. Am J Hum Genet 1995; 60: 19–26.

  230. 230.

    , , , et al. A case-control family history study of autism. J Child Psychol Psychiatry 1994; 35: 877–900.

  231. 231.

    , , . Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J Child Psychol Psychiatry 2005; 46: 963–971.

  232. 232.

    . Diagnosis of autism spectrum disorders in the first 3 years of life. Nat Clin Pract Neurol 2008; 4: 138–147.

  233. 233.

    , , , , . Parents' perceptions of autism spectrum disorder etiology and recurrence risk and effects of their perceptions on family planning: recommendations for genetic counselors. J Genet Couns 2010; 18: 507–519.

  234. 234.

    , , , et al. The UCLA-University of Utah epidemiologic survey of autism: prevalence. Am J Psychiatry 1989; 146: 194–199.

Download references

Author information


  1. Division of Medical Genetics, Department of Child Health, Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri Hospitals and Clinics, Columbia, Missouri

    • Judith H Miles


  1. Search for Judith H Miles in:

Corresponding author

Correspondence to Judith H Miles.

About this article

Publication history





Further reading