E472 Full

REVIEW ARTICLE
The Genetics of Autism
Rebecca Muhle, BA*; Stephanie V. Trentacoste, BA*; and Isabelle Rapin, MD
ABSTRACT. Autism is a complex, behaviorally de- tribution of a few well characterized X-linked disorders,
fined, static disorder of the immature brain that is of male-to-male transmission in a number of families rules
great concern to the practicing pediatrician because of an out X-linkage as the prevailing mode of inheritance. The
astonishing 556% reported increase in pediatric preva- recurrence rate in siblings of affected children is 2% to
lence between 1991 and 1997, to a prevalence higher than 8%, much higher than the prevalence rate in the general
that of spina bifida, cancer, or Down syndrome. This population but much lower than in single-gene diseases.
jump is probably attributable to heightened awareness Twin studies reported 60% concordance for classic au-
and changing diagnostic criteria rather than to new en- tism in monozygotic (MZ) twins versus 0 in dizygotic
vironmental influences. Autism is not a disease but a (DZ) twins, the higher MZ concordance attesting to ge-
syndrome with multiple nongenetic and genetic causes. netic inheritance as the predominant causative agent.
By autism (the autistic spectrum disorders [ASDs]), we Reevaluation for a broader autistic phenotype that in-
mean the wide spectrum of developmental disorders cluded communication and social disorders increased
characterized by impairments in 3 behavioral domains: 1) concordance remarkably from 60% to 92% in MZ twins
social interaction; 2) language, communication, and and from 0% to 10% in DZ pairs. This suggests that
imaginative play; and 3) range of interests and activities. interactions between multiple genes cause idiopathic
Autism corresponds in this article to pervasive develop- autism but that epigenetic factors and exposure to envi-
mental disorder (PDD) of the Diagnostic and Statistical ronmental modifiers may contribute to variable expres-
Manual of Mental Disorders, Fourth Edition and Interna- sion of autism-related traits. The identity and number of
tional Classification of Diseases, Tenth Revision. Except genes involved remain unknown. The wide phenotypic
for Rett syndromeattributable in most affected indi- variability of the ASDs likely reflects the interaction of
viduals to mutations of the methyl-CpG-binding protein multiple genes within an individuals genome and the
2 (MeCP2) genethe other PDD subtypes (autistic disor- existence of distinct genes and gene combinations among
der, Asperger disorder, disintegrative disorder, and PDD those affected. There are 3 main approaches to identify-
Not Otherwise Specified [PDD-NOS]) are not linked to ing genetic loci, chromosomal regions likely to contain
any particular genetic or nongenetic cause. Review of 2 relevant genes: 1) whole genome screens, searching for
major textbooks on autism and of papers published be- linkage of autism to shared genetic markers in popula-
tween 1961 and 2003 yields convincing evidence for mul- tions of multiplex families (families with >1 affected
tiple interacting genetic factors as the main causative family member); 2) cytogenetic studies that may guide
determinants of autism. Epidemiologic studies indicate molecular studies by pointing to relevant inherited or de
that environmental factors such as toxic exposures, ter- novo chromosomal abnormalities in affected individuals
atogens, perinatal insults, and prenatal infections such as and their families; and 3) evaluation of candidate genes
rubella and cytomegalovirus account for few cases. These known to affect brain development in these significantly
studies fail to confirm that immunizations with the mea- linked regions or, alternatively, linkage of candidate
sles-mumps-rubella vaccine are responsible for the surge genes selected a priori because of their presumptive con-
in autism. Epilepsy, the medical condition most highly tribution to the pathogenesis of autism. Data from
associated with autism, has equally complex genetic/non- whole-genome screens in multiplex families suggest in-
genetic (but mostly unknown) causes. Autism is frequent teractions of at least 10 genes in the causation of autism.
in tuberous sclerosis complex and fragile X syndrome, Thus far, a putative speech and language region at 7q31-
but these 2 disorders account for but a small minority of q33 seems most strongly linked to autism, with linkages
cases. Currently, diagnosable medical conditions, cytoge- to multiple other loci under investigation. Cytogenetic
netic abnormalities, and single-gene defects (eg, tuber- abnormalities at the 15q11-q13 locus are fairly frequent
ous sclerosis complex, fragile X syndrome, and other rare in people with autism, and a chromosome 15 pheno-
diseases) together account for <10% of cases. There is type was described in individuals with chromosome 15
convincing evidence that idiopathic autism is a herita- duplications. Among other candidate genes are the
ble disorder. Epidemiologic studies report an ASD prev- FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-
alence of 3 to 6/1000, with a male to female ratio of 3:1. q33 and the GABAA receptor subunit and UBE3A genes
This skewed ratio remains unexplained: despite the con- on chromosome 15q11-q13. Variant alleles of the seroto-
nin transporter gene (5-HTT) on 17q11-q12 are more fre-
From the *Class of 2004, Albert Einstein College of Medicine, Bronx, New quent in individuals with autism than in nonautistic
York; and Saul R. Korey Department of Neurology, Department of Pedi- populations. In addition, animal models and linkage
atrics, and Rose F. Kennedy Center for Research in Mental Retardation and data from genome screens implicate the oxytocin receptor
Human Development, Albert Einstein College of Medicine, Bronx, New at 3p25-p26. Most pediatricians will have 1 or more chil-
York. dren with this disorder in their practices. They must
Received for publication Aug 27, 2002; accepted Dec 1, 2003. diagnose ASD expeditiously because early intervention
Ms Muhle and Ms Trentacoste contributed equally to this work.
increases its effectiveness. Children with dysmorphic
Address correspondence to Isabelle Rapin, MD, Albert Einstein College of
Medicine, K 807, 1300 Morris Park Ave, Bronx NY 10461. E-mail:
features, congenital anomalies, mental retardation, or
[email protected] family members with developmental disorders are those
PEDIATRICS (ISSN 0031 4005). Copyright 2004 by the American Acad- most likely to benefit from extensive medical testing and
emy of Pediatrics. genetic consultation. The yield of testing is much less in
e472 PEDIATRICS Vol. 113 No. 5 May 2004 http://www.pediatrics.org/cgi/content/full/113/5/e472

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high-functioning children with a normal appearance and Asperger disorder (language development at the ex-
IQ and moderate social and language impairments. Ge- pected age, no mental retardation), 3) disintegrative
netic counseling justifies testing, but until autism genes disorder (behavioral, cognitive, and language regres-
are identified and their functions are understood, prena- sion between ages 2 and 10 years after entirely nor-
tal diagnosis will exist only for the rare cases ascribable mal early development, including language), 4) PDD
to single-gene defects or overt chromosomal abnormali- not otherwise specified (individuals who have autis-
ties. Parents who wish to have more children must be
told of their increased statistical risk. It is crucial for
tic features and do not fit any of the other subtypes),
pediatricians to try to involve families with multiple and 5) Rett disorder (a genetic disorder of postnatal
affected members in formal research projects, as family brain development, caused by a single-gene defect
studies are key to unraveling the causes and pathogene- predominantly affecting girls).
sis of autism. Parents need to understand that they and The highly variable cognitive manifestations of the
their affected children are the only available sources for ASDs range from a nonverbal child with severe men-
identifying and studying the elusive genes responsible tal retardation and self-injury9 to a high-functioning
for autism. Future clinically useful insights and potential college student with an above-average IQ despite
medications depend on identifying these genes and elu- impaired language use and inadequate social skills.10
cidating the influences of their products on brain devel- Mental retardation thus is not a defining criterion for
opment and physiology. Pediatrics 2004;113:e472e486. autism (albeit certain cognitive abilities are charac-
URL: http://www.pediatrics.org/cgi/content/full/113/
teristically affected), but the mean distribution of IQs
5/e472; autism, genetic, chromosome, review.
is lower than average,11 and the likelihood of retar-
dation increases with more widespread brain dys-
ABBREVIATIONS. ASD, autistic spectrum disorder; PDD, perva- function.12 Mental retardation is itself a behaviorally
sive developmental disorder; MMR, measles-mumps-rubella; defined disorder of complex human abilities with
DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth
Edition; ICD-10, International Classification of Diseases Tenth Revi-
many genetic and nongenetic causes. The more se-
sion; TSC, tuberous sclerosis complex; FXS, fragile X syndrome; vere the retardation, the more likely the underlying
AS, Angelman syndrome; PWS, Prader-Willi syndrome; MZ, brain dysfunction will affect the widely distributed
monozygotic; DZ, dizygotic; LD, linkage disequilibrium; GABA, networks responsible for sociability, language, and
-amino butyric acid; IMGSAC, International Molecular Genetic cognitive flexibility.
Study of Autism Consortium; MLS, multipoint logarithm of the
odds score; DBH, dopamine hydroxylase; Hox, homeobox; OT, Like mental retardation, autism is a behaviorally
oxytocin. defined syndrome with a wide variety of both ge-
netic and nongenetic causes. With the exception of
Rett syndrome, which is caused in the majority of
A
utism, also known as autistic spectrum dis- cases by de novo mutations or microdeletions of the
order (ASD) or pervasive developmental methyl-CpG-binding protein 2 (MeCP2) gene on
disorder (PDD), is of great concern to the Xq28,13 there is no current evidence that the other
practicing pediatrician. The US Department of De- DSM-IV subtypes of autism are linked to any partic-
velopmental Services reported a 556% increase in the ular genetic or nongenetic disorder. Therefore, when
prevalence of autism from 1991 to 1997,1 a rate that is we refer in this article to autism, we are referring to
higher than the prevalence rates reported for other the entire spectrum of behaviorally defined autism
pediatric disorders such as spina bifida, cancer, and with the exception of Rett syndrome. Current evi-
Down syndrome.2 Likely explanations for this aston- dence indicates that multiple genetic factors are the
ishing increase include the inclusion of broader cri- causative determinants of the majority of cases of
teria for the diagnosis of ASD and physicians in- autism.14
creased awareness of ASD symptoms.3 Although the
media have focused attention on the measles- METHODS
mumps-rubella (MMR) vaccine and, more recently, We performed a comprehensive search of Medline using the
mercury poisoning as potential causes of autism, terms autism, autistic, gene, genome, genomic, ge-
epidemiologic studies to date have shown no correl- netic, chromosome, chromosomal, and loci in various
ative associations.4,5 Greater public awareness of combinations. These queries returned 500 citations. We re-
viewed papers published between 1961 and 2003, focusing on
autism has led to increased funding for autism re- scientific articles published between 1995 and 2003. After study of
search, yet the cause of ASD remains largely un- these papers, we performed additional searches to examine spe-
known because of the complex behavioral pheno- cific topics (eg, autism, oxytocin) not included in the initial set.
types and multigenic etiology of this disorder.6 We also reviewed 2 current definitive textbooks concerned with
According to the Diagnostic and Statistical Manual of autism: Cohen and Volkmar15 and Gillberg and Coleman.9
Mental Disorders, Fourth Edition, Text Revision (DSM-
IV-TR)7 and International Classification of Diseases, RESULTS
Tenth Revision (ICD-10)8 classifications, autism is Defined Nongenetic and Genetic Medical Conditions
characterized by impairments in 3 behavioral do- Associated With Autism
mains: 1) social interaction; 2) language, communi- Autism has been linked to a wide variety of pre-
cation, and imaginative play; and 3) range of inter- natal and postnatal insults but predominantly in in-
ests and activities.7 Assignment to 1 of 5 subtypes is dividual case reports or short series. In the aggregate,
based on the number and distribution of endorsed they account for only a small percentage of cases.9,16
behavioral descriptors in each of the domains, as Obstetric complications (eg, an increased incidence
well as on the age at onset. The 5 DSM-IV PDD of uterine bleeding) have often been blamed for au-
subtypes are 1) autistic disorder (classic autism), 2) tism17 despite that many studies show no significant
http://www.pediatrics.org/cgi/content/full/113/5/e472 e473
causal relationship.18,19 Intrauterine exposure to the retardation, autism, and epilepsy has exhibited early
teratogenic drugs thalidomide and valproate have bilateral hippocampal sclerosis.38,39
been implicated as the cause of autism in a few Behavioral symptoms of autism are frequent in
affected children.20,21 Mean levels of some of the tuberous sclerosis complex (TSC) and fragile X syn-
neuropeptides substance P, vasoactive intestinal drome (FXS), but these 2 disorders nevertheless ac-
peptide, pituitary adenylate cyclase-activating count for only a minority of the total cases of au-
polypeptide, calcitonin gene-related peptide, and tism.40,41 Given the high rate of epilepsy in children
neurotrophin nerve growth factor, the concentration with TSC and the association between autism and
of all of which is under genetic control, were elevated epilepsy, it is perhaps not surprising that as many as
in the cord blood of children who later received a 25% of patients with TSC have autism.42,43 An auto-
diagnosis of autism or mental retardation22; they somally dominant neurocutaneous disorder, TSC
were normal in nonautistic children with cerebral arises from genetic mutations of either TSC1 on 9q or
palsy, which generally results from an abnormal in- TSC2 on 16p and is characterized by ash-leaf depig-
trauterine environment or peri-/postnatal insult mented or other cutaneous manifestations and
rather than a genetic condition. Maternal factors hamartomatous lesions in multiple organs. In the
have also been examined as potential causes of au- brain, these lesions are termed tubers, and they are
tism; antibodies in the sera of a mother of 2 children, thought to cause the epilepsy seen in more than three
one with autism and another with severe language quarters of children with TSC.44,45 Furthermore, it is
impairment, were shown to bind to the cerebellar the haphazard distribution of these tubers, together
cells of developing fetal mice.23 There is no evidence with other metabolic changes, that influences the
in population surveys of any association between phenotype of TSC, giving rise in some individuals to
autism and immigrant status, socioeconomic status, autism or epilepsy (often infantile spasms).37 In the
or ethnicity.16 population of patients with autism, numerous stud-
Various epidemiologic studies have reported that ies have quoted TSC rates of 1.1% to 1.3%,2527,46
cerebral palsy, defined as a static motor deficit of rates that, although low, are 30% higher than the
brain origin present from early life, is present in 2.1% prevalence of TSC in the general population.
to 2.9% of individuals with autism and mental retar- FXS is an X-linked genetic disorder that is signifi-
dation.2427 Congenital rubella infection, initially cantly associated with autism and that is denoted by
found to be highly associated with autism,28 is unusual facial features, macro-orchidism in adult-
present in only 0.75% of recent autistic populations,24 hood, and cognitive impairment of variable severity.
thanks to the near eradication of rubella after the It is caused by an increased number of trinucleotide
introduction of quasi-universal immunization in (CGG) repeats in the gene coding for the fragile X
Western countries. Other pre- and postnatal infec- mental retardation protein. Approximately 30% of
tions by organisms such as Haemophilus influenzae individuals with FXS are on the autistic spec-
and cytomegalovirus can cause autism when they trum.47,48 There is disagreement, however, over the
significantly damage the immature brain.9 degree of FXS prevalence in patients with autism.
In a review of several epidemiologic studies of Some early studies reported little or no association
autism, Fombonne24 found no association between between FXS and autism,24,49 whereas others found a
autism and inflammatory bowel disease or with a high association50 (see41 for additional review). More
live MMR vaccination. This contradicts an earlier recent epidemiologic studies have documented rates
publication by Wakefield et al.29 Large surveys that of FXS between 7% and 8% in populations with
have examined the prevalence of autism before and autism.26,33,51,52 The discrepancies regarding the
after the initiation of widespread MMR vaccination prevalence of FXS among individuals with autism
have also failed to corroborate an association with may reflect the limited reliability of the cytogenetic
autism4,5 but have not reassured a skeptical public of tests used in the past compared with the more sen-
the safety of the vaccine.30 Some investigators pos- sitive molecular tests currently used; as such, the
tulate that it is the mercury-based preservative number of girls who receive a diagnosis of FXS has
thimerosal in vaccines, rather than the vaccines increased.6
themselves, that poses a risk to the developing in- Genetic mutations that give rise to a number of
fant.31 This theory has also met with significant crit- additional diagnosable diseases may also be associ-
icism.32 ated with autism. Neurofibromatosis, a common au-
Epilepsy has the highest association with autism, tosomal dominant disorder with neurologic and cu-
reported in up to a third of individuals with an ASD taneous manifestations, is much less frequently
by adulthood.2527,3335 The epilepsy may be subclin- associated with autism than is TSC or FXS.53 An-
ical, yielding an electroencephalogram that is epilep- gelman syndrome (AS) and Prader-Willi syndrome
tiform but without clinical seizures, and is particu- (PWS) usually result from genetic deletions or uni-
larly frequent in disintegrative disorder.36 Like parental disomy (inheritance of both chromosomes
autism, epilepsy is a disorder of the brain with mul- from 1 parent) of the chromosome 15q11-q13 lo-
tiple genetic and nongenetic causes and a broad cus,54,55 with abnormal imprinting or genetic muta-
range of phenotypes. Infantile spasms are particu- tions found in up to 5.1% of PWS cases and up to
larly likely to result in autism with nondevelopment 15% of AS cases.55 Loss of paternally derived genes
of language and mental retardation, especially when results in PWS, whereas AS, more commonly associ-
the epileptiform activity involves both temporal ated with autism than PWS,56,57 can result from the
lobes.37 An occasional nonverbal child with mental loss or mutation of the maternally derived ubiquitin
e474 GENETICS OF AUTISM

protein ligase gene UBE3A or the ATP10C gene.5860 population.9,27,46 Second, early twin studies in the
An unexpectedly large proportion of boys with United Kingdom and Scandinavia reported that
Duchenne muscular dystrophy are on the autistic monozygotic (MZ) twins had a rate of concordance
spectrum.61 Many other rare single-gene defects 60% for classic autism, with no concordance found
have been associated with autism in case studies, between dizygotic (DZ) twins.76,77 The higher rate of
including those found in Sotos syndrome,62 Williams MZ concordance provides compelling evidence for
syndrome,63 hypomelanosis of Ito,64 Cowden syn- the strong influence of genetics in the cause of au-
drome,65 and Moebius syndrome.66,67 We refer the tism, influence that extends well beyond the afore-
reader to The Biology of the Autistic Syndromes by mentioned associated genetic disorders. Further-
Gillberg and Coleman (p. 136 184)9 for a more com- more, when the unaffected twin discrepant for
plete listing of rare genetic conditions that are re- autism was reevaluated for broader autistic pheno-
sponsible for autism in occasional individuals. types, including communication skills and social dis-
Finally, autism may also occur in the context of orders, the concordance among the UK twins rose
abnormal cellular metabolism, such as mitochondrial remarkably, from 60% to 92% in MZ twins and from
disease or dysfunction.68,69 Untreated phenylketonu- 0% to 10% in DZ pairs.76,84 The existence of a sus-
ria is a well-documented metabolic cause of au- ceptible genetic background is also suggested by the
tism7072; however, whether this is attributable to the preponderance of traits such as obsessive-compul-
resulting severe mental retardation or to the specific sive disorder, communication disorders, and social
deficit in the dopamine pathway is uncertain.73 Some phobias in nonautistic family members of patients
clinic-based studies report high levels of uric acid with autism.8587 These crucial observations suggest
secretion in up to one quarter of patients with autism that the interactions of multiple genes cause autism
and amelioration of certain symptoms with antihy- and that there is variable expression of autism-re-
peruricosuric metabolic therapy.74 This represents a lated traits.
significant proportion of these clinical samples, but it Surprising disparity in some MZ twin pairs who
has not been widely replicated and the genes that are share 100% of their genes and are concordant for
responsible for this type of purine autism remain diagnosis indicates that other factors can modify
to be identified. these phenotypes. For example, 2 MZ twin girls with
Although the links between autism and these di- Joubert syndrome were concordant for most of its
agnosable conditions are often convincing, we em- classic manifestations and underlying brain malfor-
phasize that the total number of individuals who are mation but were dramatically discordant for autism:
on the autistic spectrum and have known genetic or only the more severely affected twin, with a much
nongenetic conditions is only a small percentage of more extensive cerebellar anomaly, had autism. This
the whole9,14,24 and that an association with autism is informative case study illustrates the range of possi-
not universal in any 1 of the diagnosable medical or ble phenotypes expressed by an identical genetic
genetic conditions mentioned. In population-based background.88 Because each MZ twin was exposed to
studies of children with autism, they account for a a variety of pre-, peri-, and postnatal environmental
small minority, probably 10%, of individuals with modifiers, differences in their phenotypes suggests
autism.16,25,27,75 The vast majority of individuals with that as-yet-undefined environmental factors were en-
autism do not have any 1 of these infrequent nonge- countered by only 1 of them and that the multifac-
netic or rare genetic causes, yet family studies indi- torial influence of a susceptible genetic background
cate that genetics play the major causative role in and random environmental stresses may be neces-
most individuals with idiopathic autism.6,76,77 sary for full expression of the disorder. Alternatively,
1 of the discrepant MZ twins may have sustained a
Inherited Autism of Unknown Cause: Family Studies random epigenetic mutation in early embryonic life
Epidemiologic studies of autism report a preva- that altered the expression of the genetic trait.
lence of 510 cases of classic autism per 10 000 (some Despite the evidence from twin and family studies,
3 6 per 1000 if the entire spectrum of autism is the identity and number of genes involved are not
included) with a male to female ratio of 3:1.3,9,11 The yet known. Data from whole-genome screens in mul-
preponderance of males suggests an X-linked disor- tiplex families (families with more than a single af-
der, and recent genome-wide screens by 2 separate fected family member) strongly indicate that 10 or
groups have found evidence of linkage to the X more genes interact to cause autism.89,90 Cytogenetic
chromosome,78,79 but the data are inconsistent. Cases abnormalities in individuals with autism have been
of male-to-male transmission of autism in multiplex found on virtually every chromosome.83 Autism,
families, however, rule out X-linkage as the predom- therefore, seems to be multigenic in that similar au-
inant mode of inheritance in these families.80,81 Sim- tistic phenotypes may arise from different genes or
ilarly, analysis of Y haplotypes in patients with au- gene combinations in different families. An example
tism showed no significant associations,82 although of single-mutation genetic heterogeneity is tuberous
Y chromosome abnormalities have been documented sclerosis caused by TSC1 on chromosome 9q in some
in case reports.83 families and TSC2 on 16p in others. In addition,
There is strong and convincing evidence from 2 autistic disorders are polygenic; that is, several syn-
main sources that autism without a diagnosable ergistically acting genes in an affected individuals
cause is a heritable disorder. First, the rate of recur- genome may be required to produce the full autistic
rence in siblings of affected individuals is 2% to 8%, phenotype. Thus, in individuals with autism, certain
much greater than the prevalence rate in the general sets of genes acting in concert have lowered a theo-
retical threshold to allow the development of autism of mutations in the gene sequence or relative levels
either by themselves or, in some cases, given the of expressed protein. Association studies use poly-
right set of environmental or immunologic modifi- merase chain reaction to amplify putative candidate
ers.91 Family members with other related develop- genes and search for mutations to determine whether
mental disorders (but not diagnosable autism) can be a polymorphism (a change in the typical genetic
presumed to have inherited some of the susceptibil- sequence that may or may not be expressed as a
ity genes found in the affected family member or to functional mutation) within a gene shows a signifi-
have the same set of susceptibility genes but without cant association with the disease. RNA hybridization
exposure to the same environmental trigger factors and protein blots can be performed to identify the
for autism. relative levels of the gene product. In addition, the
creation of animal models through targeted gene
The Search for Candidate Genes disruption or mutation provides a complementary
A number of approaches are being used to eluci- approach to unraveling the pathophysiology of the
date the association between specific genes and au- disorder.
tism (Fig 1). Whereas genome screens search for
common genetic markers in populations of multiplex Cytogenetics and Chromosomes 15q and 7q
families with autism, cytogenetic studies search for Cytogenetic assays have long been used to un-
inherited or spontaneous genetic abnormalities on an cover chromosomal defects in patients with autism,
individual basis. Additional investigations, referred and a number of cytogenetic abnormalities besides
to as linkage disequilibrium (LD) studies, are per- fragile X have been described.9 Although 10% of
formed to narrow the search region identified by cases of autism are associated with chromosomal
cytogenetic analysis or genome screen or to examine abnormalities,92,93 high-resolution cytogenetic scans
linkage to a specific gene. LD refers to the inheritance in families with affected individuals help to locate
of a particular allele more frequently in the affected specific genes or chromosomal regions (loci) poten-
family members than would be expected by chance tially associated with the ASDs. Using various stains,
and is assessed using DNA sequences called micro- the chromosomes of patients with autism are ana-
satellite markers. The statistically significant finding lyzed for visible breakpoints, translocations, duplica-
of 1 or more markers to a greater extent in the af- tions, and deletions. These regions are then scruti-
fected population denotes the inheritance of a sus- nized for the presence of genes that potentially are
ceptibility allele. Finally, hypothesis-driven research involved in the pathogenesis of ASD.
is a fundamentally different approach in that several Cytogenetic abnormalities found at the 15q11-q13
candidate genes are chosen a priori for additional locus are reported most frequently in patients with
study on the basis of a plausible pathogenetic model autism, up to 1% to 4%.83,9396 Various population
of autism. The ultimate goal of all of these techniques studies and case reports have described duplica-
is to identify heritable genetic mutations in candidate tions,93,9699 deletions,93,95 and inversions100,101 at
genes that predispose an individual to autism or to this locus. Duplications can occur as interstitial tan-
traits associated with autism. Candidate genes that dem repeats (such that multiple copies of this locus
are involved in the cause of autism are genes whose are present in the chromosome) or as a supernumer-
product is known to play a role in brain development ary isodicentric chromosome 15 (an extra chromo-
or to be associated with brain structures, neurotrans- some 15 with 1 or 2 copies of the chromosome 15q11-
mitters, or neuromodulators implicated in autism on q13 region), leading to trisomy or tetrasomy of genes
the basis of previous research findings. at the 15q11-q13 locus.54 Inherited duplications are of
Once candidate genes have been identified, af- maternal origin,69,93,97,102,103 and seem to cause au-
fected individuals and age-, gender-, and ethnically tism by creating an overabundance of product from
matched control subjects are tested for the presence the nonimprinted (and therefore not silenced) mater-
Fig. 1. The search for candidate

genes. Investigators use various ex-
perimental techniques and patho-
physiologic models of autism to iden-
tify candidate genes. The relevance of
these genes to autism pathogenesis is
determined by the use of experimen-
tal methods to assess the biological
activity, expression, and allelic associ-
ations in populations with autism and
their families.

nally derived genes. Several investigators have de- the 7q22-q33 locus. A recent report analyzed the
scribed a chromosome 15 phenotype in individu- chromosome 7 breakpoints of 3 patients with autism.
als with chromosome 15 duplications, characterized These breakpoints localized to 3 different regions
to variable degrees by ataxia, language delay, epi- and affected the genes FOXP2, neuronal pentraxin 2
lepsy, mental retardation, and facial dysmorphol- (NPTX2), and a noncoding RNA transcript labeled
ogy.101,103 The manifestations of this phenotype over- TCAG_4133353.119 NPTX2 is thought to be involved
lap with the autistic phenotype, giving credence to in excitatory synaptogenesis and localizes to chromo-
the involvement in ASD pathogenesis of a gene or some 7q22.1. Both FOXP2 and TCAG_4133353 are
genes in this region. mutated in patients with speech and language disor-
The cytogenetic abnormalities of chromosome ders, and therefore the 7q31-q33 region is designated
15q11-q13 point to several gene targets for additional a putative language and speech locus.125,126 Disor-
study. The -amino butyric acid (GABAA) receptor ders of language and communication are a core fea-
gene cluster (which contains genes for 3 of the recep- ture of the autistic phenotype,7 and studies show that
tors subunits: GABRB3, GABRA5, and GABRG3) is family members of individuals with autism have
strongly implicated in the pathogenesis of autism, higher rates of communication and social difficulties
given its involvement in the inhibition of excitatory than control subjects.125,127 The FOXP2 gene muta-
neural pathways and its expression in early devel- tion was identified in a genetic analysis of a large
opment.104 Mice deficient in GABRB3 have epilepsy nonautistic British family with developmental lan-
and electroencephalographic abnormalities, as well guage and speech disorders.128 Although the pre-
as learning and memory deficits reminiscent of senting family members do not have autism and the
ASD.105,106 LD studies have also pointed to the in- relevance of the FOXP2 gene to autism is disput-
volvement of the GABAA cluster. Two groups indeed,129 the subsequent finding of a breakpoint in the
pendently found LD with marker 155CA-2 near FOXP2 gene in a patient with autism is an important
GABRB3,96,107 but attempts to replicate these find- result confirming the presumed involvement of
ings in other populations have failed.95,108111 Other FOXP2. Other genes in the 7q31-q33 region include
groups have found LD to other markers near the IMMP2L, identified as the site of a chromosomal
GABRB3 gene108,112 or near the GABRG3 gene.111 breakpoint in a patient with Tourettes syndrome
Another gene at the 15q11-q13 locus is the mater- and autism,130 and RAY1/ST7, which was inter-
nally derived AS gene UBE3A.113,114 The expression rupted by a translocation breakpoint in a boy with
of UBE3A is predominantly in the human brain, and autism.131 Researchers are currently performing as-
it is regulated by complex mechanisms involving sociation studies on these and other genes to validate
imprinting and possibly silencing by antisense RNA these findings.
transcribed from the paternal chromosome.95,98,115 In
a screen of an autistic population using markers Whole-Genome Searches
spanning a known translocation region at 15q11-q13, Cytogenetic techniques, although valuable in case
investigators found LD with a marker at the 5 end of studies to delineate probable regions of interest, can-
the UBE3A gene, providing additional support for a not identify specific genes in affected individuals
link between the AS gene and autism.95 Reports that with a normal karyotype. Investigators apply ge-
individuals who harbor an abnormal chromosome nome-wide screening technology to uncover specific
15q11-q13 do not always develop an ASD,116 how- chromosomal regions that affected individuals in-
ever, suggest that mutation of these genes is not herit more often than predicted by chance. These
sufficient to cause autism and again points to the studies entail multiplex family screening using mic-
requirement for multiple susceptibility genes on dif- rosatellite markers. The DNA analysis of the affected
ferent chromosomes. family members and their first-degree affected/un-
Chromosomal translocations have also implicated affected relatives identifies loci that co-segregate
the q22-q33 region of chromosome 7.83,117119 The with the particular condition, a phenomenon termed
protein reelin (RELN), which localizes to a site of linkage. Linkage of a putative autism susceptibility
chromosomal translocation at 7q22, is a large se- gene with a microsatellite marker results in de-
creted glycoprotein potentially involved in neural creased recombination at that locus during meiosis
migration during development.120 It is of particular because of their proximity to each other. As the
interest given that it binds to neuronal receptors and markers have known chromosomal locations, they
that the pathology of autism can include migration allow investigators to extrapolate the position of the
cell defects.121 Alterations in RELN protein affect postulated autism genes to create a genetic map.
cortical and cerebellar development, and the cerebel- Researchers validate the linkage by repeating the
lar neuronal abnormalities are among the more ro- screens using markers at a higher density. A physical
bust pathologic findings in autism.122 Persico et al123 map can then be created by DNA isolation and se-
reported an association between individuals with quencing to identify candidate genes (for additional
autistic disorder and a long trinucleotide repeat information, see132134). Fortunately, the Human Ge-
polymorphism in the 5 region of the RELN gene, nome Project has already sequenced many regions of
and Western blot analysis of postmortem cerebellar the genome, thereby making sequencing unneces-
cortices from 5 individuals with autism demon- sary in some cases and allowing rapid identification
strated a 44% reduction in RELN protein levels as and investigation of candidate genes.135
compared with 8 nonautistic control subjects.124 In the first published genome-wide screen for au-
Numerous other genes are under investigation at tism-associated genes, the International Molecular
Genetic Study of Autism Consortium (IMGSAC) ob- a specific marker at 7q31-q33, and researchers pos-
tained DNA samples from 99 multiplex autistic fam- tulated the existence of an autism susceptibility lo-
ilies and looked for evidence of linkage to 354 differ- cus, termed AUTS1, in affected family members.
ent polymorphic microsatellite markers.136 IMGSAC Beyer et al140 constructed a physical map of this
identified 6 regions of interest (Table 1) with a mul- region, mapping 23 genes to the site, and Scherer et
tipoint logarithm of the odds score (MLS) 1.0. (The al119 recently published the annotated sequence of
MLS ratio assesses the likelihood that the marker and the entire chromosome, thereby providing specific
the autism locus are indeed linked, or are unlinked if sequence data for subsequent candidate gene inves-
the presumed linkage data are insignificant.) Accord- tigations.
ing to Lander and Kruglyak,137 an MLS score be- Given that the ASDs display significant clinical
tween 3.0 and 3.6 is highly significant for genetic heterogeneity, analysis of particular behavioral phe-
linkage, whereas scores 3.0 are weak associations. notypes exhibited by probands (the affected present-
None of the MLS scores obtained by IMGSAC in the ing family members) and their relatives might ex-
initial study reached this threshold. However, anal- pose susceptibility alleles involved in the
ysis of a more epidemiologically homogeneous pop- pathogenesis of these specific autism-related traits
ulation subset that included only UK families uncov- that would be otherwise weak in a screen of a phe-
ered a significant MLS score of 3.55 at the notypically heterogeneous population of multiplex
chromosome 7q locus. Table 1 shows the results of a families. Researchers with the Collaborative Linkage
later study that reexamined the sample group with Study of Autism hypothesized that inclusion of mul-
an additional 69 multiplex families. This follow-up tiplex families selected for a specific autistic pheno-
study verified linkage findings on chromosomes 7q type would uncover the genetic basis of these partic-
and 16p and found additional sites of linkage on ular behavioral deficits. By selecting autistic
chromosomes 2q and 17q.138 Therefore, although probands with both impaired and delayed acquisi-
linkage data can seem weakly significant in a single tion of language and speech production as well as a
study, the examination of more homogeneous pop- family history of difficult or late development of
ulations and the inclusion of a larger number of language or reading, they found increased linkage to
study subjects can increase the significance of the the putative speech and language locus on chromo-
initial findings. Of course, replication in independent some 7q.141 The MLS for linkage to the 7q31-q33
samples is essential to validate these data.132,134 locus rose from 1.4 in the mixed sample to 2.2 in this
IMGSAC performed an additional study in 2001 to impaired-language subtype of autism, whereas the
evaluate the chromosome 7 locus more closely.139 linkage score at this locus in a group of probands
They screened 170 multiplex families (91 from the who did not exhibit language disorders decreased
original study plus 79 additional families) using a from 1.4 to 0.1. The Collaborative Linkage Study of
higher density of markers targeting the 40-cM region Autism also demonstrated linkage to chromosome
identified in the previous study. Multipoint linkage 13q in the group selected for language difficulty.
analysis showed linkage with a high MLS of 3.37 to Studies by others have shown evidence of increased
linkage to chromosome 2q in other populations with
language difficulty.142,143 A similar approach was
TABLE 1. Linkage Data From Sequential Studies by the used to show increased linkage to the chromosome
IMGSAC Group* 15q11-q13 locus in probands and families with repet-
Chromosome IMGSAC, 1998 (136) IMGSAC, 2001 (138) itive movement disorders or stereotypies.144 This re-
sult is particularly exciting, given that although chro-
Location (cM) MLS Location (cM) MLS
mosome 15q11-q13 cytogenetic abnormalities are
1 225.21 0.58 highly associated with autism, genome screens to
255.59 0.6 date have reported only weak linkages.78,145
2 103 0.65 24.3 0.39
111.43 1.6 Additional targeted studies have corroborated
206.39 3.74 linkage to the autism susceptibility locus AUTS1 on
4 4.8 1.55 0 0.71 7q31-q33,117,141,146 and linkage to this locus is the
140.57 0.44 most highly replicated finding in the genome scans
230.15 0.43
7 144.7 2.53 119.6 3.2
performed to date (Table 2). Although the MLS
10 51.9 1.36 53.66 1.08 scores have been variable (0.833.2), the importance
64.29 1.43 of this region is reinforced by the documented trans-
13 85 0.59 locations in patients with autism. The AUTS1 locus
15 34.1 0.76 contains several potential genes, including the afore-
40.46 0.65
16 17.3 1.51 16.7 1.59 mentioned FOXP2, RAY1/ST7, and IMMP2L, as well
21.8 2.12 as the glutamate receptor GRM8,147 CADPS2,148 and
23.1 2.93 WNT2.149 The WNT2 gene codes for an evolutionar-
17 45.37 2.34 ily conserved glycoprotein that is part of a develop-
19 48.2 0.99 63.02 0.13
22 5 1.39 41.43 0.33
mentally important signaling pathway.150 Mice har-
boring a WNT2 protein signaling defect display
* The theoretical genetic distance between recombination events is reduced social interaction and aberrant behaviors
expressed in morgans (M), which represent the distance between
2 loci such that on average 1 crossing over will occur per meiosis.
reminiscent of autism.151 Researchers have found 2
Linkage studies use the centimorgan (1 cM 0.01 M), which on different WNT2 mutations in multiplex families with
average contains 1 million base pairs. autistic disorder.149 Additional tests revealed that a

TABLE 2. Genetic Sites of Putative Autism Susceptibility Loci, as Determined by Genomic Screens*
Chromosome Location Highest Studies Demonstrating Candidate Genes (Partial Listing)
Locus (cM) LOD Score Additional Linkage
(ref) Data
1p 149 2.63 (153) 89, 142, 221
2q32 200 3.74 (138) 78, 142 DLX1/DLX2 (HOX genes), secretin receptor (SCRT), Cd28/
ctla4 (involved in celiac disease)
3p25-p26 190 2.88 (153) 78 OT receptor
5q 45 2.55 (79) 142
6q21 120 2.23 (145) Glutamate receptor (GRIK2/GLUR6)
7q22 111 3.2 (138) 79 Reelin (RELN), neuropentraxin 2 (NPTX2), HOXA1
7q31-q33 144 2.53 (136) 78, 89, 139, 142, 153, 222 FOXP2, IMMPL2, RAY1/ST7, WNT2, PEG/MEST
13q 55 3.0 (222)
15q11-q13 43 1.1 (145) 78, 138 GABAA receptor (GABRB3), ubiquitin protein ligase (UBE3A)
16p13 23.1 2.93 (138) 79, 136 NMDA receptor, tuberous sclerosis complex (TSC2)
17 45 2.34 (138)
19p 52 2.46 (79) 78, 136, 142, 145
X 82 2.67 (79) 78
NMDA indicates N-methyl-d-aspartate.
* The highest reported linkage (reference in italics) is listed followed by the reference numbers of any additional studies documenting
linkage scores 1.0 to the same site. Sites with no reported linkage score 2.0 were not included (with the exception of chromosome
15q11-q13).
variable DNA sequence adjacent to the WNT2 gene Hypothesis Driven Studies: The Search for Candidate
increased the risk of autism by 50% in proband sib- Genes
ling pairs and trios. It is unclear, however, whether Cytogenetic assays and whole-genome screens are
the mutation affects the expression of other genes in techniques for identifying relevant genes without
the locus or whether the mutation will be found in a reliance on an a priori hypothesis of autism patho-
wider autistic population. Indeed, a subsequent re- physiology. As just discussed, the hope is that these
port did not find an association between WNT2 and empirical studies may highlight genes involved with,
autism.152 for example, language impairment, neurotransmitter
Besides FXS and Rett syndrome, the X chromo- defects, or metabolic abnormalities in autism that
some has been putatively implicated as a cause of would otherwise be overlooked. In contrast, hypoth-
autism, but only recently have genome studies pub- esis-driven studies predict the involvement of certain
lished data in support of its involvement. Genome candidate genes on the basis of clinical and empirical
screens by 2 separate groups have found linkage to evidence. A researcher might see an alleviation of
the Xq13-q21 region that contains the neuroligin ASD symptoms with certain pharmacologic inter-
genes.78,79,153 Neuroligins are cell-adhesion mole- ventions and then look for differences in the genes
cules potentially involved in synaptogenesis.154 Most that regulate the corresponding endogenous metab-
recently, a group in France has identified mutations olites in affected patients as compared with control
of the neuroligins NLGN3 (at Xq13) and NLGN4 (at subjects. Association studies are crucial in this type
Xp22.3) in a screen of 158 multiplex ASD families. of research, as they examine polymorphisms in can-
Two families exhibited maternal transmission of a didate genes selected without previous evidence
mutated neuroligin allele to affected male offspring: from cytogenetic or genome analysis but because
a de novo truncation of NLGN4 and a mutation there is empirical evidence that the gene product(s)
compromising the functional structure of NLGN3.155 may be implicated in the pathogenesis of the disor-
Evidence of an association between a new X-linked der. Serotonin reuptake inhibitors, dopamine antag-
form of mental retardation and mutations of the onists, and some adrenergic drugs have favorable
angiotensin II receptor gene (AGTR2) on Xq22-q23 is effects on the behavioral symptoms of autism158;
relevant given that 2 of 9 subjects with mental retar- therefore, the genes that code for the receptors or
dation also had autism.156 The importance of these neurotransmitters of these substances are targets for
data is corroborated by previous case study findings these types of genetic studies.
of deletions at the Xp22.3 locus in individuals with Serotonin is pivotal during development and if
autism157 and the high rate of mental retardation in altered may contribute to structural brain abnormal-
patients with autism.16 The Rett syndromeassoci- ities and to the core behavioral characteristics of
ated gene MeCP2 is located at the Xq28 locus, but autism.159,160 Studies have long shown a 30% to 50%
studies have not yet shown that it plays a role in the increase in platelet serotonin levels in some individ-
pathogenesis of idiopathic autism.150,151 uals with autism,161 but investigators have not yet
Other linkages to potential autism susceptibility found the physiologic basis for this well-documented
loci have been identified on all but 7 chromosomes phenomenon. The serotonin transporter gene
(Table 2). Although some linkages may not survive (5-HTT) has been examined in several different pop-
the study of larger cohorts, the number of loci iden- ulations. Whereas Cook et al162 found preferential
tified to date supports the multigenic and polygenic inheritance of a short promoter variant of the 5-HTT
theories of autism inheritance. gene in affected individuals, others reported that a
long promoter variant of the 5-HTT transporter was ment that pinpoint the time of injury to the closure of
inherited more frequently by affected family mem- the neural tube.179 The physical abnormalities of the
bers.163,164 Still another group found that neither brain include an absence of cranial motor nuclei and
long nor short promoter alleles were preferentially shortening of the brainstem, which are very similar
inherited by individuals with autism but that the to the congenital malformations caused by deletions
short promoter variant was associated with a clinical of homeobox (Hox) genes.180 Hox genes regulate
phenotype of increased severity.165 These data are hindbrain development, differentiation of the uro-
contradicted by reports of little or no association genital system, and appendicular skeletal growth.
between autism and the serotonin transporter pro- They include the genes HOXA1 on chromosome
moter variants in other autistic populations.166170 7p15, HOXB1 on chromosome 17q, and HOXD1 on
Dopamine-blocking agents, such as Haldol, are the chromosome 2q31.179,181 Abnormalities of the
oldest and most effective drugs for treating the core HOXA1 gene may give rise to genetic forms of the
symptoms of autism, although their potentially irre- Moebius syndrome,180 which is highly associated
versible motor and other side effects drastically limit with autism.182 One group found aberrant forms of
their use.158 There is evidence of abnormal dopami- HOXA1 and HOXB1 in a survey of autistic fami-
nergic activity in the low medial prefrontal cortex of lies,179 but this was contradicted by additional stud-
children with autism,171 as well as elevated levels of ies.183185 This does not rule out the involvement of
catecholamines in the blood, urine, and cerebrospi- other Hox genes as causes of autism, however. Man-
nal fluid of some children with autism.172,173 Genetic ning et al186 reported a lower ratio of second to
studies have examined the dopamine receptors D2, fourth digit length in families with autism, possibly
D3, and D5; the tyrosine hydroxylase gene; and the reflecting derangement of prenatal testosterone lev-
dopamine hydroxylase gene (among others) but els as a result of mutations in HOXA13 or HOXD13.
with few results.172,174 One patient with autism ex- Furthermore, the Hox genes DLX1 and DLX2 lie at
hibited a missense mutation in the DRD5 gene, but chromosome 2q32,187 which is a site of significant
the relevance to the wider clinical population is un- linkage in genomic screens.138
known.175 In addition to serotonin and dopamine, recent ev-
The dopamine hydroxylase (DBH) gene, which idence suggests that the neurotransmitter acetylcho-
maps to chromosome 9q34, encodes a protein that line may be associated with autism. Chemical and
catalyzes the conversion of dopamine to norepineph- histochemical studies showed a reduction in the
rine, a key player during embryonic neural develop- number of the neuronal -4 nicotinic acetylcholine
ment. In a study of multiplex autistic families, re- receptor subunits in postmortem parietal neocortex
searchers found no increased concordance for DBH and cerebellum of individuals with autism when
alleles among affected siblings. However, they found compared with normal control subjects and individ-
that reductions in the level of maternal dopamine uals with mental retardation without autism.188,189
hydroxylase significantly increased the risks of au- This receptor is linked to chromosome 20q13.2-
tism in her offspring. Mothers of multiple children q13.3,190 a locus thus far unexplored in autism genet-
with autism had a higher frequency of DBH alleles ics but linked to several epilepsy syndromes and
containing a 19-bp deletion (DBH) when compared schizophrenia.191
with matched control subjects.176 The attributable Recently, researchers have begun to examine the
risk of autism (ie, the rate of disease in exposed glutamatergic system in the pathogenesis of autism.
individuals that can be attributed to a DBH allele) Several lines of evidence suggest the involvement of
was 42%, suggesting a strong correlation between glutamate receptors: 1) symptoms of hypoglutama-
autism and homozygous DBH mothers. The dele- tergia mimic the behavioral phenotypes of autism192;
tion was associated with decreased maternal enzyme 2) serotonin receptor 2A (5-HT2A) agonists cause
activity, which in turn causes decreased levels of behavior similar to autism, perhaps via expression of
norepinephrine and increases levels of dopamine in 5HT2A on glutamatergic-inhibiting GABAergic neu-
utero. Reduced DBH activity in these women, how- rons193; 3) association studies have implicated the
ever, may yet reflect another underlying genetic dis- involvement of GABAA receptors on 15q11-q13 that
order, which causes the observed reduction in DBH in turn modulate glutamatergic function107; and 4)
activity but may cause a predisposition to autism in excessive glutamatergic activity is associated with
the offspring through different, undetermined mech- epileptiform activity, which is highly associated with
anisms.177 autism.194 Although these theories are putative and
Specific chemical insults in utero can lead to long- even contradictory, several studies have reinforced
lasting physiologic imbalances of neurotransmitters, the involvement of the glutamate system. Upregu-
and the diagnosis of an ASD in such patients rein- lated expression of the glutamate transporter gene
forces the neurotransmitter imbalance model of au- was found in postmortem studies of autistic brain
tism. Mice exposed on embryonic day 9 to valproate tissue195 and in the striatum of a dopamine-depleted
or thalidomide, documented causative agents of au- mouse model of autistic behavior.196 The inotropic
tism, display increased concentrations of serotonin in glutamate receptor 6 (GluR6) gene on chromosome
plasma and the hippocampus and greater levels of 6q21 was associated significantly with autism by LD
dopamine in the frontal cortex than controls at 4 and multipoint linkage analysis, and a surveyed au-
weeks of age.178 Thalidomide exposure on days 20 to tistic population possessed a single amino acid sub-
24 postconception in humans causes autism as well stitution in GluR6 to a greater degree than a control
as specific abnormalities in ear and limb develop- population.197 Finally, the metabotropic glutamate

receptor GRM8 in the chromosome 7q31-q33 autism language deficits, delays, or regressions should be
susceptibility locus has exhibited LD with autism.147 addressed promptly and thoroughly, and pediatri-
These data highlight the need for additional investi- cians should not delay investigation of abnormal
gations into the relationship between the glutamate development because they want to avoid placing
system and autism. additional stress on the family.2 There are various
The potential relevance of endogenous opiates to screening tests for autistic behaviors, such as the
autism comes from animal models that indicate its Checklist for Autism in Toddlers213 and the Perva-
influence on sociability. Administration of exoge- sive Developmental Disorder Screening Test,214 but
nous morphine agonists to rats enhances social play, there is no definitive medical or biological test for
whereas treatment with antagonists reduces it.198 Im- autism. Few children with autism have diagnosable
aging studies of the rats brains showed an increase diseases such as TSC, FXS, Rett syndrome, or AS.9,15
in opiate peptide release during social play,199 and These specific causes and others must be investi-
prenatal exposure to morphine elevated the level of gated when the family history or examination sug-
social play and grooming in juvenile pups.200 The gests them, but in most individuals the cause of the
relevance of these opiate studies to autism is not autism remains unidentifiable at present.210
clear, however; although impaired sociability is a Although physicians must diagnose ASD
core symptom of autism,201 it is often associated with promptly in their patients to provide proper treat-
a high threshold for pain, which suggests an abnor- ment, we emphasize that tests for the many but rare
mally high (not low) level of endogenous opiates. genetic conditions reported in association with au-
Indeed, Willemsen-Swinkels et al202 found that tism are stressful, costly, and often unavailable out-
plasma -endorphin levels were elevated in individ- side a research project. DNA studies are expensive
uals who have autism and exhibit severe self-injuri- and have a very low yield unless the family history,
ous behavior, and the widely used opiate antagonist medical history, presence of mental retardation, or
naltrexone may have some limited utility for treating dysmorphic or other findings on examination sug-
the self-injurious behaviors associated with au- gest a diagnosable condition. The benefit of testing
tism.203 Evidence of a genetically based opiate defi- for a high-functioning child with a normal appear-
ciency or overexpression in individuals with autism ance and IQ and moderate social and language im-
is currently lacking, however. pairment is minimal.215 Testing may be useful for
The neuromodulator oxytocin (OT) is also poten- genetic counseling but rarely leads to a meaningful
tially relevant to the impaired sociability of autism. change in the affected childs management. Children
OT is a nonapeptide that affects human parturition with abnormal features on physical examination are
and lactation. Investigators have determined that OT 10-fold more likely than those without them to have
levels affect social behavior in rats, mice, and prairie a diagnosable genetic condition.33,216 Findings such
voles.204206 Postulating the involvement of OT in the as micro- or macrocephaly, abnormal finger digit
pathophysiology of autism, Modahl et al207 found ratios, and posteriorly rotated ears are associated
significantly lower overall plasma OT levels in chil- with various developmental abnormalities of the
dren with autism versus age-matched control sub- brain and mental retardation.46,186,209,217,218 Because
jects. Subsequently, the ratio of the inactive OT pre- the yield of specific diagnoses is highest in children
cursor (OT-X) to active OT peptide was found to be with cognitive impairment or congenital anomalies,
significantly higher in children with autism than in we recommend, for routine clinical care, limiting
control subjects.208 These findings point to additional extensive testing to those with a suspicious family or
candidate genes for investigation, including the pro- medical history, mental retardation, or dysmorphol-
hormone convertases PC2 and PC5 that convert OT ogy46,209,215,219,220 and to families who wish to have
precursor to OT, the OT peptide variants themselves, additional children, as different genetic disorders
and the OT receptor. Two recent genome-wide have different recurrence risks.219
screens have found significant linkage in autism to It is therefore important for pediatricians to be able
the chromosome 3p25-p26 locus containing the OT to educate families regarding recurrence risks. A sur-
receptor gene.78,153 Although intriguing, no genome vey conducted at the New England Medical Center
scan performed to date has shown evidence of link- found that parents are confused about the causes of
age to the OT gene locus itself on chromosome autism but would like prenatal testing and diagno-
20p13. sis.30 It is necessary to inform parents of the known
causes of autism and that, whereas prenatal diagno-
DISCUSSION sis is possible in the case of defined disorders such as
In light of the high prevalence of children with an FXS, there is no prenatal test to identify idiopathic
ASD, pediatricians are likely to have 1 or more chil- autism. Given the recurrence rate of 2% to 8% in
dren with this disorder in their practices. Awareness siblings of affected children and that the initial diag-
of the symptoms and causes of autism therefore is nosis of autism is made between 1 and 4 years of age,
relevant to the pediatrician in several ways. First, the it is especially important to offer parents information
spectrum of causes and presentations of the ASDs about their recurrence risks before they conceive an-
are confusing and complicate diagnosis, yet physi- other child.219 Physicians must also be attentive to
cians must recognize autism expeditiously.209 Re- the psychological concerns of the family and be pre-
search has shown that early diagnosis and interven- pared to inform the parents of individuals with au-
tion significantly improve a childs long-term tism about available state and federal services.212
outcome.210212 Parental reports of early social or For research purposes, exhaustive causative inves-
tigations in families who have given informed con- so difficult. It invites much additional work in an
sent are required to exclude known associated con- exciting yet daunting area of research.
ditions that might cloud the interpretation of the
data. It is crucial for pediatricians to try to involve
ACKNOWLEDGMENTS
families with multiple affected members in such for-
We thank Dr Laurie Ozelius for reviewing an earlier draft and
mal projects, as family studies are key to unraveling 3 anonymous reviewers for helpful suggestions.
the causes of autism. Many families must be
screened to untangle the subtle genetic differences
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Rebecca Muhle, Stephanie V. Trentacoste and Isabelle Rapin
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Rebecca Muhle, Stephanie V. Trentacoste and Isabelle Rapin
Pediatrics 2004;113;e472
DOI: 10.1542/peds.113.5.e472
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2004 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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The Genetics of Autism

Rebecca Muhle, BA; Stephanie V. Trentacoste, BA; and Isabelle Rapin, MD

e472 PEDIATRICS Vol. 113 No. 5 May 2004 http://www.pediatrics.org/cgi/content/full/113/5/e472

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