Papel de Genetista en El Autismo
-
Upload
josue-barral -
Category
Documents
-
view
6 -
download
0
description
Transcript of Papel de Genetista en El Autismo
-
American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 160C:104110 (2012)
A R T I C L E
Working Up Autism:The Practical Role of Medical GeneticsFIORELLA GURRIERI1*
The autism spectrum disorders (ASD) comprise a group of neurobehavioral phenotypes of heterogeneousetiology. In spite of a worldwide extensive research effort to unravel the genetic mystery of autism, medicalgeneticists are still facing an embarrassing lack of knowledge in dealing with the diagnosis, and consequentlyprognosis, of a child with autism. However, some lessons can be learned from accumulating experience in theclinical and molecular genetic evaluation of children with this condition. Patient evaluation, indications formolecular testing and counseling are the three aspects that will be discussed in this review.
2012 Wiley Periodicals, Inc.
KEYWORDS: autism spectrum disorders; molecular tests; physical examination; genetic counseling; CGH microarray
How to cite this article: Gurrieri F. 2012. Working up autism: The practical role of medical genetics.Am J Med Genet Part C Semin Med Genet 160C:104110.
INTRODUCTION
Autism spectrum disorders (ASD)
include a group of neurobehavioral
conditions that have in common im-
pairment in socialization and communi-
cation, restriction and peculiarity of
interests and stereotypic behavior
[DiCicco-Bloom et al., 2006]. The
diagnosis is usually made no earlier
than 18 months without upper limits
(41 months on average) [Autism and
Developmental Disabilities Monitoring
Network Surveillance Year 2000 Prin-
cipal Investigators; Centers for Disease
Control and Prevention, 2007]. ASD
affects about 1:110 children, with a
4:1 male/female ratio. In about 70% of
cases the onset is gradual whereas in the
remaining 30% it is of regressive nature.
In spite of the more or less stringent
diagnostic criteria established by the
Diagnostic and Statistical Manual of
Mental Disorders, 4th edition (DSMIV)
[American Psychiatric Association
only because the clinical spectrum is
highly variable, but also because the phe-
notype may evolve and change over
time. For example, language, which is
usually delayed, can be developed at a
good level in 10% of ASD children, or
can remain mildly impaired in about
30%. On the other hand, 10% of
children develop no language at all and
40% have severely impaired language
[Howlin et al., 2004]. Along the same
line, about 20% of ASD children end up
in a regular school program, still with
some social impairment, whereas the
majority (up to 75%) remain within the
autistic spectrum phenotype; only a small
percentage (no more than 5%) may
completely recover [Zappella, this issue].
In addition, ASD is commonly as-
sociated with other medical issues,
such as epilepsy (about 30% of cases)
[Tuchman and Rapin, 2002], intel-
lectual disability (between 30% and
80%) [Fombonne, 1999; Chakrabarti
and Fombonne, 2005] and attention def-
icit hyperactivity disorders (ADHD),
which add complexity to the clinical
picture and make it difcult to reach a
causal diagnosis, without which there is
no possible clue to prognosis and family
counseling.
Therefore, it is crucial to fully com-
prehend the patients presentation both
at the neuropsychological, developmen-
tal, and behavioral picture. In addition to
that, laboratory testing, to detect possi-
ble genetic and metabolic alterations, is
also a relevant part of the diagnostic
work-up in ASD.
The purpose of thiswork is to brief-
ly describe the inuence of genetic and
environmental factors in ASD, and to
put more emphasis on aspects of the
clinical genetic evaluation, molecular
diagnosis, and counseling.
CLINICAL GENETICEVALUATION
Once the neuropsychological diagnosis
of an ASD disorder is established, it
is crucial to proceed with a medical
examination in order to detect con-
comitant issues that require treat-
ment. Among those, seizures, feeding
and gastrointestinal problems, sleep
Fiorella Gurrieri is associate professor of Medical Genetics at the Catholic University of Rome,School ofMedicine. She is involved in clinical andmolecular genetics.Her research is focusedon thegenetic aspects of autismand specically she has investigated quantitative andqualitative genomicalterations and their phenotypic consequences. A second research eld includes the application ofnew genomic technologies to identify the causes of congenital defects.
*Correspondence to: Fiorella Gurrieri, Istituto di Genetica Medica, Universita` Cattolica delS. Cuore, L.go F. Vito 1, 00168 Roma, Italy. E-mail: [email protected]
DOI 10.1002/ajmg.c.31326Article rst published online in Wiley Online Library (wileyonlinelibrary.com): 12 April 2012
2012 Wiley Periodicals, Inc.
-
disturbances and dental abnormalities
[Olivie, 2012].
In addition, a clinical genetics eval-
uation should be considered in ASD
children in order to identify syndromic
forms of autism, identify familial cases,
and drive diagnostic testing.
This workup has been recom-
mended by the American Academy of
Pediatrics [Johnson and Myers, 2007]
and the American College of Medical
Genetics [Schaefer and Mendelsohn,
2008; Shen et al., 2010; Roesser, 2011].
The rst duty of the clinical geneti-
cist in evaluating a child with autism is to
dissect the etiologic heterogeneity of
ASD by distinguishing essential autism
from complex (syndromic) autism
[Miles, 2011].
Essential autism is usually present in
about 75% of cases and is characterized
by absence of dysmorphic features,
higher male-to-female ratio (6:1),
higher sibling recurrence risk (up to
35%) and positive family history (up to
20% of cases).
Essential autism is usually
present in about 75% of cases
and is characterized by absence
of dysmorphic features, higher
male-to-female ratio (6:1),
higher sibling recurrence risk
(up to 35%) and positive
family history
(up to 20% of cases).
Complex, syndromic autism is usually
characterized by recognizable dysmor-
phic features, lower male-to-female
ratio (3.51), lower sibling recurrence
risk (46%), less frequent positive family
history (up to 9%) [Miles, 2011]. In this
latter group the prognosis is usually
worse.
The distinction between essential
and complex autism is important
because it implies a different prognosis
and a different recurrence risk for other
family members. In spite of all these
recommendations not all ASD children
usually undergo a clinical genetic evalu-
ation, but mainly those with evident
dysmorphic features, positive family his-
tory and intellectual disability.
As it turns out, this is not the best
practice, because in selected cases of
nonsyndromic ASD the recurrence
risk might be actually higher and parents
should be informed that the phenotype
in a second child can be even more
severe than in their rst child.
An additional duty of the clinical
geneticist is to collect information on
the family history in order to identify
in other relatives the occurrence of phe-
notypes that can be related to ASD. For
instance, family history can be positive
for alcoholism, depression, manic-de-
pression, obsessivecompulsive disor-
ders, substance abuse, seizures, anxiety
disorders, Tourrette-like motor tics, an-
orexia. These ndings occur in up
to 35% of ASD families [Miles et al.,
2003]. To investigate on family history
is important because the identication
of additional relatives in the ASD spec-
trum is suggestive of a higher recurrence
risk for the siblings of the proband.
On the other hand, the nding of an
environmental exposure reduces the re-
currence risk for the family, provided
that the environmental risk factor is
removed.
The clinical genetic evaluation can
recognize phenotypes related to known
genetic conditions such as fragile X syn-
drome, Rett syndrome, tuberous sclero-
sis, Angelman syndrome, SmithLemli
Opitz syndrome and others. This recog-
nition is crucial to drive appropriate
molecular testing.
On the other hand, the general
practice of testing all ASD patients for
FMR1mutations without a proper clin-
ical evaluation only yields positive results
in less than 0.5% of cases [Roesser,
2011]. It should also be kept in
mind that in most monogenic forms of
essential ASD, such as those caused by
mutations in neuroligins, neurexines,
SHANK3, FOXP2 and many others
[Miles, 2011] there is no recognizable
phenotype that drives the testing to-
wards one gene or another.
GENETIC FACTORS
ASD is one of the most heritable neu-
ropsychiatric disorders, with an in-
creased recurrence risk (more than 20-
fold) in rst-degree relatives [Bayley
et al., 1995]. This observation points
to a major genetic contribution. How-
ever, despite signicant research, includ-
ing high throughput technique
applications, efforts have failed to iden-
tify genes of large-effect, whose identi-
cation could impact strongly the
diagnosis, prognosis, and counseling to
ASD families. The outstanding question
is: Where is the heritable component of
autism?
So far, more than 100 genes and 40
genomic loci have been reported in re-
lation to ASD [Betancur, 2011] and as-
sociated/overlapping phenotypes such
as intellectual disability, ADHD, epilep-
sy, and schizophrenia. None of these
genes, however, is responsible by itself
for a high percentage of cases of ASD.
Therefore, it is suggested that multiple
genes (of minor effect) in combination
with environmental factors, contribute
to this complex neurobehavioral pheno-
type. Because of this wide genetic het-
erogeneity, the diagnostic yield of single
gene testing strategies is quite low (less
than 1%).
In some cases, ASD is part of the
phenotypic expression of a single-gene
disorder, while in others it results from a
combination of common genetic factors
that add up to overcome a threshold. In
the former situation, a clinical diagnosis
needs to be done rst, in order to rec-
ognize the basic disorder and determine
proper molecular testing. Even an oli-
gogenic inheritance of multiple hypo-
morphic mutations in genes whose
severe alterations cause known genetic
syndromes (TSC1 and 2, UBE3A,
PTEN, MECP2, and SHANK3) has
been observed in ASD [Schaaf et al.,
2011]. This observation suggests a new
genetic model for ASD.
In general genetic alterations re-
sponsible for ASD can be classied
into three subgroups: cytogenetic alter-
ations detectable on standard karyotype
(up to 5%), copy number variants
(CNVs), which can be found in a
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 105
-
variable percentage of cases (between
10% and 35%), and single gene muta-
tions (less than 5%) [Miles, 2011].
Abnormalities of the standard kar-
yotype are commonly found in ASD
patients with dysmorphic features and
intellectual disability [Reddy, 2005].
These abnormalities have been reported
in almost all chromosomes with the
same frequency, except for the duplica-
tion of the 15q11-q13 region in the
form of inv dup (15), which seem
more specically associated with ASD
[Dykens et al., 2004]. This duplication
occurs in about 13% of patients, but its
incidence might be higher because some
interstitial duplications of this same
region can only be detected with
array-CGH.
Other classical chromosomal syn-
dromes, such as Down syndrome (up
to 7% of cases) and Turner syndrome,
as well as other sex chromosome disor-
ders have been associated with autism
[Creswell and Skuse, 1999; Kent et al.,
1999].
Submicroscopic alterations (CNVs)
can be found in about 10% of patients
from simplex families and less than 2% of
patients from multiplex ones [Sebat
et al., 2007]. About 7% are de novo.
Again, one expects to identify such
CNVs mostly in syndromal autism.
One main distinction that needs to be
made is between pathogenic CNVs
(usually de novo, large and with signi-
cant gene-content), polymorphicCNVs
(usually inherited, small and with poor
gene-content). A third category
includes CNVs of unknown clinical sig-
nicance (medium sized, with signi-
cant gene-content, usually inherited
from a parent with a border-line pheno-
type). The most common ASD-related
CNVs are the 15q11-q13 duplication,
the 7q21 deletion, and the 16p11.2
microdeletion with its reciprocal micro-
duplication [Weiss et al., 2008], but oth-
er ones are being recurrently reported.
All CNVs specically associated with
ASD are annotated in a dedicated data-
base at projects.tcag.ca/autism_500k/:
with the highest stringency, a total of
276 CNVs result as being specic for
ASD in this database.
Because in some instances the same
CNVs have been associated with vari-
able phenotypes including autism,
atypical autism, schizophrenia, dyslexia,
intellectual disability, ADHD and
others, it is likely that these represent
predisposing genomic alterations lead-
ing to a variable nal phenotype corre-
lated with the genetic background and
the environment.
The last group of genetic alterations
in ASD includes single gene disorders.
Unless there is a recognizable clinical
diagnosis, such as fragile X, Angelman
or Rett syndrome, the likelihood of
identifying a single gene mutation in a
nonsyndromic ASD patient is extremely
low. A list of clinically recognizable sin-
gle gene disorders frequently associated
with ASD is reported in Table I.
With respect to fragile X syndrome,
both FMR1 full mutations and pre-
mutations can be found in children
with ASD: it is estimated that 13% of
ASD childrenmay have alterations in the
FMR1 gene. This is not surprising con-
sidering the overlapping of the neuro-
behavioral phenotypes in ASD and
fragile X syndrome.
Rett syndrome is also frequently
associated with autism: MECP2 muta-
tions are reported in approximately 1%
of children diagnosed with autism. On
the other hand, about 18% of girls end-
ing upwith a diagnosis ofRett syndrome
are initially considered autistic.
Among other single gene disorders,
tuberous sclerosis is frequently associated
with ASD with 25% of patients fullling
the diagnostic criteria for autism [Baker
et al., 1998]; the frequency of autistic
features is higher in younger children, up
to 60% [Jeste et al., 2008], and decreases
as the child gets older.
Mutations in the PTEN gene have
also been detected in 18% (according to
different studies) of children with ASD
TABLE I. Clinically Recognizable Single Gene Disorders in Which Autism Is Frequently Reported
Syndrome Gene locus % ASD among patients
Fragile X FMR1 Up to 30%
PTEN extreme macrocephaly PTEN n.a.
Rett syndrome MECP2 Up to 18%
Tuberous sclerosis TSC1 and TSC2 50%
Timothy syndrome CACNA1C and CACNA1F High
Phenylketonuria PAH 6%
Creatine biosynthesis and transport disorders SLC6A8 Up to 80%
L-arginine:glycine amidinotransferase
Guanidinoacetate methyltransferase
SmithLemliOpitz syndrome 7-Dehydrocholesterol reductase 5080%
Sotos syndrome NSD1 n.a.
Moebius syndrome Unknown 30%
Duchenne muscular dystrophy Dystrophin
PhelanMcDermid syndrome SHANK3 Up to 90%
106 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
-
and extreme macrocephaly [Buxbaum
et al., 2007; Varga et al., 2009].
Another gene which is likely
to cause a recognizable syndromic au-
tism, is SHANK3. Heterozygous muta-
tions and intragenic deletions have been
reported in about 15% of patients with
ASD, epilepsy, tendency to overgrowth,
hypotonia, and absent language [Her-
bert, 2011]. A complete deletion of
this gene is observed in the Phelan
McDermid syndrome, which is caused
by a microdeletion of several genes on
the 22q13 region.
Among the genetic factors, inborn
errors of metabolism should also be
included:
Mitochondrial disorders can be detected
in 45% of ASD children even with-
out additional neurological issues
[Hass, 2010].
Phenylketonuria, adenylosuccinase lyase
deciency, creatine deciency syn-
dromes usually show behavioral alter-
ations overlapping with autistic
symptoms in addition to severe intel-
lectual disability and seizures [Van den
Berghe et al., 1997; Baieli et al., 2003;
Newmeyer et al., 2007].
SmithLemliOpitz syndrome is proba-
bly the condition most frequently as-
sociated with ASD: variable features
of the spectrum can be detected in up
to 80% of these patients [Sikora et al.,
2006].
In addition, it has been repeatedly
suggested that individuals gifted with
mathematical minds might be
more likely to have a child with
ASD [Baron-Cohen, 2006; Buchen,
2011].
It should also be taken into account
that an increasing number of genes,
whose mutations are associated with
autism, are being annotated. In a recent
review on the genetics of ASD a list
of the most signicant genes involved
in this condition was reported [Miles,
2011]. This list has rapidly grown
as more and more genes have been
identied either by candidate gene
approach [Schaaf et al., 2011] or
through exome sequencing of trios
(proband parents) [ORoak et al.,
2011]; however, none of thesemutations
has led to a clinically distinguishable
phenotype.
ENVIRONMENTALFACTORS
It has been widely observed that there
has been an increase in incidence of ASD
over the past years. However, it is still
debated whether this increase is related
to a diagnostic improvement, raised
awareness towards ASD, or to emerging
environmental factors, not present in the
past, that have inuenced this epidemi-
ologic change [Duchan and Patel, 2012].
If this is the case, it is crucial to recognize
these factors because they are the ones
most amenable to elimination.
Environmental risk factors may be
related to in utero exposure: for instance,
children whose mothers consumed
antiepileptic drugs have a sevenfold in-
creased risk for ASD [Palac and
Meador, 2011]; maternal alcohol con-
sumption is also a risk factor [Eliasen
et al., 2010]. Emphasis has been placed
also on oxytocin levels at delivery:
lower levels seem to reduce the capabili-
ty to socialize and to increase the
risk for communication impairment
[Gurrieri and Neri, 2009; Gregory
et al., 2009].
Assisted reproductive technologies
or short interval between pregnancies
may represent additional risk factors
[Zachor and Ben Itzchak, 2011].
Other environmental modiers in-
clude advanced paternal age (risk in-
creased 2.2 times with paternal age
>50) [Hultman et al., 2011], oxidativestress and environmental pollutants (such
as air pollution, organophosphates, and
heavy metals).
Epilepsy, food intolerance, immune
and hormonal dysfunction, mitochon-
drial and metabolic unbalance (i.e., low
glutathione, low antioxidant and detox-
icant activity) epigenetic modications
[Grafodatskaya et al., 2010] and the
microbiome composition also play a
role in ASD, but it is difcult to establish
whether these issues are primarily
involved in its etiology or rather repre-
sent concomitant medical problems
[Herbert, 2010].
All these factors need to be consid-
ered when collecting anamnestic data in
ASD children.
MOLECULAR DIAGNOSISAND TESTING STRATEGIES
More than half (between 50% and 70%)
of the parents have the perception that
the cause of ASD in their children might
be of genetic nature [Harrington et al.,
2006; Selkirk et al., 2009]. It is crucial for
the clinical geneticist to assess the
parents expectations of genetic testing
and to inform them of the limited utility
of the genetic testing in providing
answers or suggesting treatment plans.
In order to determine appropriate
biochemical and molecular testing, a
clinical genetic evaluation is crucial or
unnecessary effort will be put into the
search of a genetic or organic (metabol-
ic) cause in each ASD patient. Evenwith
an extensive clinical workup, physicians
can expect to identify a genetic cause in
less than 25% of ASD patients.
After clinical genetic evaluation one
can expect three possible scenarios: the
patient has nonsyndromic autism, a spe-
cic genetic syndrome is suspected,
or the patient has morphological alter-
ations on physical exam, but a specic
genetic condition cannot be identied.
After clinical genetic
evaluation one can expect
three possible scenarios: the
patient has nonsyndromic
autism, a specic genetic
syndrome is suspected, or the
patient has morphological
alterations on physical exam,
but a specic genetic condition
cannot be identied.
In the case of essential autism, al-
though a genetic basis is possible, no
specic test for monogenic ASD should
be recommended because the possibility
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 107
-
of identifying a pathogenic mutation is
negligible. Only array-CGH testing is
worthwhile because there is a 10%
chance of identifying a possibly patho-
genic CNV [Sebat et al., 2007]. Standard
karyotype is the rst step when array-
CGH is not available, even in essential
autism, otherwise the latter should be
the rst choice. The diagnostic yield
of standard cytogenetic testing is about
2% [Roesser, 2011].
It has been shown that the highest
diagnostic yield among the different
laboratory tests is reached by array-
CGH. There have been variable
reports of different authors who have
identied CNVs in a percentage of
ASD cases varying from 10% [Sebat
et al., 2007] to 18% [Shen et al., 2010].
It has been shown that the
highest diagnostic yield among
the different laboratory tests is
reached by array-CGH. There
have been variable reports of
different authors who have
identied CNVs in a
percentage of ASD cases
varying from 10% to 18%.
It should bementioned that the results of
array-CGH are not always easy to inter-
pret: for instance, the sameCNVs can be
detected in an ASD child and his/her
healthy or border-line parent or a de
novo CNV can have a nonsignicant
gene content so that it is difcult to
consider it pathogenic. Also, potentially
detrimental CNVs detected in ASD can
be also be found, although at a lower
frequency, in the normal population.
Interpreting array-CGH can be a very
difcult task that should be left to expe-
rienced medical geneticists.
Not infrequently, array-CGH in
ASD patients detects CNVs commonly
associated with specic microdele-
tion or microduplication syndromes:
among those, the 22q11 deletion (asso-
ciated with DiGeorge velo-cardio-facial
syndrome), the 17p11 deletion (associ-
ated with SmithMagenis syndrome),
the 22q13 deletion (associatedwith Phe-
lanMcDermid syndrome) or even the
MECP2 duplication (for which there is
no specic phenotype). In these cases the
phenotypic expression of the known
syndrome is atypical and therefore not
easily recognizable.
For children with normal results on
array-CGH I would not recommend
further testing but follow-up and even-
tually propose autism-specic-gene se-
quencing, when such diagnostic tools
will become available and affordable.
Fragile X testing is frequently rec-
ommended as a rst step molecular test
in ASD. However, in cohorts not
screened by clinical evaluation the diag-
nostic yield is quite low: less than 0.5%
[Reddy, 2005].
Figure 1 shows a possible diagnostic
itinerary in ASD patients.
COUNSELING
If a genetic cause of clear pathogenic
signicance is identied, the recurrence
risk for sibs is relatively easy to establish
according to the etiologic diagnosis. If
no genetic alteration is found, and this
happens in the majority of patients,
an empirical 1020% risk for sibs
should be given [Ozonoff et al., 2011].
If a genetic cause of clear
pathogenic signicance is
identied, the recurrence risk
for sibs is relatively easy to
establish according to the
etiologic diagnosis. If no
genetic alteration is found,
and this happens in the
majority of patients, an
empirical 1020% risk for
sibs should be given.
This risk might be higher for having a
second child with milder symptoms, in-
cluding language, social, or other psy-
chiatric disorders. If the propositus has
essential autism and if there is already an
affected sib or a positive family history
the recurrence risk increases consistently
(up to 2530%) [Miles et al., 2005]. On
the other hand complex autism of un-
known etiology has a lower recurrence
risk (between 1% and 2%) [Miles, 2011].
Figure 1. Proposed genetic diagnostic itinerary for autism spectrum disorders.
108 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE
-
The medical geneticist is often re-
quired to make predictions about the
clinical outcome in case a genetic alter-
ation is or is not detected: in general
it has been observed that the prognosis
is slightly better in patients without
positive testing and with essential
autism.
FUTURE DIRECTIONS
New light has been shed recently on the
general thinking about autism: the spec-
trum is highly variable to the point
that people with autism may be particu-
larly talented in many professional set-
tings, including scientic laboratory
[Mottron, 2011]. However early diag-
nosis of this disorder is crucial as it allows
for more effective intervention so that
any talent might be more easily involved
in our social world.
It is expected that high throughput
molecular screenings, such as high reso-
lution array-CGH, exome and full ge-
nome sequencing [ORoak et al., 2011],
as well as transcriptomic analysis
[Voineagu et al., 2011] will increase
our understanding of the genetic causes
of ASD.
It will be possible in the near future
to obtain diagnostic tools to screen hun-
dreds of autism-genes in a single shot so
the genetic prole of ASD patients will
be more easily outlined. However, if we
do not correlate these ndings with a
critical evaluation of the different autistic
phenotypes, there is no way that they
will be of any help in making diagnosis,
prognosis and counseling in ASD
families.
REFERENCES
Autism and Developmental Disabilities Monitor-ing Network Surveillance Year 2000Principal Investigators, Centers for DiseaseControl and Prevention. 2007. Prevalenceof autism spectrum disordersAutism anddevelopmental disabilities monitoring net-work, six sites, United States, 2000.MMWR Surveill Summ 56:111.
American Psychiatric Association. 1994. Diagnos-tic and statistical manual of mental disorders,4th edition. Washington, DC: AmericanPsychiatric Association.
Baieli S, Pavone L, Meli C, Fiumara A, ColemanM. 2003. Autism and phenylketonuria.J Autism Dev Disord 33:201204.
Baker P, Piven J, SatoY. 1998. Autism and tuberoussclerosis complex: Prevalence and clinicalfeatures J Aut Dev Disord 28:279285.
Baron-Cohen S. 2006. The hyper-systemizing,assortative mating theory of autism. ProgNeuro-Psychopharmacol Biol Psychiatry30:865872.
Bayley A, Le Couteur A, Gottesman I, Bolton P,Simonoff E, Yuzda E, Rutter M. 1995. Au-tism as a strong genetic disorder: Evidencefrom a British twin study. Psychol Med25:6377.
Bayley A. 2011. Etiological heterogeneity inautism spectrum disorders: More than 100genetic and genomic disorders and stillcounting. Brain Res 1380:4277.
Buchen L. 2011. When geeks meet. Nature479:2527.
Buxbaum JD, Cai G, Chaste P, Nygren G,Goldsmith J, Reichert J, Anckarsater H,Rastam M, Smith CJ, Silverman JM, Hol-lander E, Leboyer M, Gillberg C, Verloes A,Betancur C. 2007.Mutation screening of thePTENgene in patientswith autism spectrumdisorders and macrocephaly. Am J MedGenet Part B 144B:484491.
Chakrabarti S, Fombonne E. 2005. Pervasivedevelopmental disorders in preschoolchildren: Conrmation of high prevalence.Am J Psychiatry 162:11331141.
Creswell C, Skuse D. 1999. Autism in associationwith Turner syndrome: Genetic implicationsfor male vulnerability to pervasive develop-mental disorders. Neurocase 5:101108.
DiCicco-Bloom E, Lord C, Zwaigenbaum L,Courchesne E, Dager SR, Schmitz C,Schultz RT, Crawley J, Young LJ. 2006.The developmental neurobiology of autismspectrum disorder. J Neurosci 26:68976906.
Duchan E, Patel DR. 2012. Epidemiology ofautism spectrum disorders. Pediatr ClinNorth Am 59:2743.
Dykens EM, Sutcliffe JS, Levitt P. 2004. Autismand 15q11-q13 disorders: Behavioral,genetic, and pathophysiological issues.Ment Retard Dev Disabil Res Rev 10:284291.
Eliasen M, Tolstrup JS, Nybo Andersen AM,Grnbaek M, Olsen J, Strandberg-LarsenK. 2010. Prenatal alcohol exposure and autis-tic spectrum disorders. A population-basedprospective study of 80,552 children andtheir mothers. Int J Epidemiol 39:10741081.
Fombonne E. 1999. The epidemiology of autism:A review. Psychol Med 29:769786.
Grafodatskaya D, Chung B, Szatmari P, WeksbergR. 2010. Autism spectrum disorders andepigenetics. J Am Acad Child AdolescPsychiatry 49:794809.
Gregory SG, Connelly JJ, Towers AJ, Johnson J,Biscocho D, Markunas CA, Lintas C,Abramson RK, Wright HH, Ellis P,Langford CF, Worley G, Delong GR,Murphy SK, Cuccaro ML, Persico A,Pericak-Vance MA. 2009. Genomic andepigenetic evidence for oxytocin receptordeciency in autism. BMC Med 7:62.
Gurrieri F,Neri G. 2009.Defective oxytocin func-tion: A clue to understanding the cause ofautism? BMC Med 7:62.
Harrington JW, Patrick PA, Brand DA. 2006.Parental beliefs about autism: Implications
for the treating physician. Autism 10:452462.
HassRH. 2010.Autism andmitochondrial disease.Dev Disabil Res Rew 16:144153.
Herbert MR. 2010. Contributions of the environ-ment and environmentally vulnerable physi-ology to autism spectrum disorders. CurrOpin Neurol 23:103110.
Herbert MR. 2011. SHANK3, the synapse andautism. N Engl J Med 365:173175.
Howlin P, Goode S, Hutton J, Rutter M. 2004.Adult outcome for children with autism.J Child Psychol Psychiatry 45:212229.
HultmanCM, Sandin S, Levine SZ, Lichtenstein P,Reichenberg A. 2011. Advancing paternalage and risk of autism: New evidence from apopulation-based study and a meta-analysisof epidemiological studies. Mol Psychiatry16:12031212.
Jeste SS, Sahin M, Bolton P, Ploubidis GB,Humphrey A. 2008. Characterization ofautism in young children with tuberous scle-rosis complex. J Child Neurol 23:520525.
Johnson CP, Myers SM, American Academy ofPediatrics Council on Children With Dis-abilities. 2007. Identication and evaluationof children with autism spectrum disorders.Pediatrics 120:11831215.
Kent L, Evans J, Sharp M. 1999. Comorbidity ofautistic spectrum disorders in children withDown syndrome. Dev Med Child Neurol41:153158.
Miles JH. 2011. Autism spectrum disordersAgenetics review. Genet Med 13:278294.
Miles JH, Takahashi TN, Haber A, Hadden L.2003. Autism families with a high incidenceof alcoholism. J Autism Dev Disord 33:403415.
Miles JH, Takahashi TN, Bagby S, Sahota PK,Vaslow DF, Wang CH, Hillman RE, FarmerJE. 2005. Essential versus complex autism:Denition of fundamental prognostic sub-types. Am J Med Genet Part A 135A:171180.
Mottron L. 2011. Changing perceptions: Thepower of autism. Nature 479:3335.
Newmeyer A, de Grauw T, Clark J, Chuck G,Salomons G. 2007. Screening of malepatients with autism spectrum disorder forcreatine transporter deciency. Neuropedi-atrics 38:310312.
Olivie H. 2012. Clinical practice: The medicalcare of children with autism. Eur J PediatrDOI: 10.1007/s00431-011-1669-1.
ORoak BJ, Deriziotis P, Lee C, Vives L, SchwartzJJ, Girirajan S, Karakoc E,Mackenzie AP,NgSB, Baker C, Rieder MJ, Nickerson DA,Bernier R, Fisher SE, Shendure J, EichlerEE. 2011. Exome sequencing in sporadicautism spectrum disorders identies severede novo mutations. Nat Genet 43:585589.
Ozonoff S, Young GS, Carter A, Messinger D,Yirmiya N, Zwaigenbaum L, Bryson S,Carver LJ, Constantino JN,DobkinsK,Hut-man T, Iverson JM, Landa R, Rogers SJ,Sigman M, Stone WL. 2011. Recurrencerisk for autism spectrum disorders: A babysiblings research consortium study. Pediatrics128:488495.
Palac S, Meador KJ. 2011. Antiepileptic drugs andneurodevelopment: An update. Curr NeurolNeurosci Rep 11:423427. Review.
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 109
-
Reddy KS. 2005. Cytogenetic abnormalities andfragile-X syndrome in Autism SpectrumDisorder. BMC Med Genet 6:3.
Roesser J. 2011. Diagnostic yield of genetic testingin children diagnosed with autism spectrumdisorders at a regional referral center. ClinPediatr 50:834843.
Schaaf CP, Sabo A, Sakai Y, Crosby J, Muzny D,Hawes A, Lewis L, Akbar H, Varghese R,Boerwinkle E, Gibbs RA, Zoghbi HY.2011. Oligogenic heterozygosity in individ-uals with high-functioning autism spectrumdisorders. Hum Mol Genet 20:33663375.
Schaefer GB, Mendelsohn NJ. 2008. Clinical ge-netics evaluation in identifying the etiologyof autism spectrum disorders. Genet Med10:301305.
Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S,Krasnitz A, Kendall J, Leotta A, Pai D, ZhangR, Lee YH, Hicks J, Spence SJ, Lee AT,Puura K, Lehtimaki T, Ledbetter D, Gre-gersen PK, Bregman J, Sutcliffe JS, Jobanpu-tra V, Chung W, Warburton D, King MC,Skuse D, Geschwind DH, GilliamTC, Ye K,Wigler M. 2007. Strong association of denovo copy number mutations with autism.Science 316:445449.
Selkirk CG, McCarthy Veach P, Lian F, Schim-menti L, LeRoy BS. 2009. Parents percep-tions of autism spectrum disorder etiologyand recurrence risk and effects of their per-ceptions on family planning: Recommenda-tions for genetic counselors. J Genet Couns18:507519.
Shen Y, Dies KA, Holm IA, Bridgemohan C,Sobeih MM, Caronna EB, Miller KJ, FrazierJA, Silverstein I, Picker J, Weissman L,Raffalli P, Jeste S, Demmer LA, Peters HK,Brewster SJ, Kowalczyk SJ, Rosen-SheidleyB, McGowan C, Duda AW III, Lincoln SA,Lowe KR, Schonwald A, Robbins M,Hisama F, Wolff R, Becker R, Nasir R,Urion DK, Milunsky JM, Rappaport L,Gusella JF, Walsh CA, Wu BL, Miller DT,Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration. 2010.Clinical genetic testing for patients with au-tism spectrum disorders. Pediatrics 125:727735.
Sikora DM, Pettit-Kekel K, Peneld J, MerkensLS, Steiner RD. 2006. The near universalpresence of autism spectrum disorders inchildrenwith Smith-Lemli-Opitz syndrome.Am J Med Genet Part A 140A:15111518.
Tuchman R, Rapin L. 2002. Epilepsy in autism.Lancet Neurol 1:352358.
Van den Berghe G, Vincent MF, Jaeken J. 1997.Inborn errors of the purine nucleotide cycle:Adenylosuccinase deciency. J InheritMetab Dis 20:193202.
Varga EA, Pastore M, Prior T, Herman GE,McBride KL. 2009. The prevalence ofPTEN mutations in a clinical pediatriccohort with autism spectrum disorders, de-velopmental delay, and macrocephaly. GenetMed 11:111117.
Voineagu I,Wang X, Johnston P, Lowe JK, Tian Y,Horvath S,Mill J, CantorRM,Blencowe BJ,Geschwind DH. 2011. Transcriptomic anal-ysis of autistic brain reveals convergent mo-lecular pathology. Nature 474:380384.
Weiss LA, Shen Y, Korn JM, Arking DE, MillerDT, FossdalR, Saemundsen E, StefanssonH,Ferreira MA, Green T, Platt OS, RuderferDM,Walsh CA, Altshuler D, Chakravarti A,Tanzi RE, Stefansson K, Santangelo SL,Gusella JF, Sklar P, Wu BL, Daly MJ, AutismConsortium. 2008. Association betweenmicrodeletion and microduplication at16p11.2 and autism. N Engl J Med 358:667675.
Zachor DA, Ben Itzchak E. 2011. Assisted repro-ductive technology and risk for autism spec-trum disorder. Res Dev Disabil 32:29502956.
110 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE