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 Genetics
FIORELLA GURRIERI1*
The autism spectrum disorders (ASD) comprise a group of neurobehavioral phenotypes of heterogeneous
etiology. In spite of a worldwide extensive research effort to unravel the genetic mystery of autism, medical
geneticists are still facing an embarrassing lack of knowledge in dealing with the diagnosis, and consequently
prognosis, of a child with autism. However, some lessons can be learned from accumulating experience in the
clinical and molecular genetic evaluation of children with this condition. Patient evaluation, indications for
molecular testing and counseling are the three aspects that will be discussed in this review.
2012 Wiley Periodicals, Inc.

KEY WORDS: 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 impairment in socialization and communication, 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 Principal 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

<!-DSMIV, 1994], the neuropsychological diagnosis is challenging not

only because the clinical spectrum is
highly variable, but also because the phenotype 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 associated with other medical issues,
such as epilepsy (about 30% of cases)
[Tuchman and Rapin, 2002], intellectual disability (between 30% and

Fiorella Gurrieri is associate professor of Medical Genetics at the Catholic University of Rome,
School of Medicine. She is involved in clinical and molecular genetics. Her research is focused on the
genetic aspects of autism and specically she has investigated quantitative and qualitative genomic
alterations and their phenotypic consequences. A second research eld includes the application of
new genomic technologies to identify the causes of congenital defects.
*Correspondence to: Fiorella Gurrieri, Istituto di Genetica Medica, Universita` Cattolica del
S. Cuore, L.go F. Vito 1, 00168 Roma, Italy. E-mail: fgurrieri@rm.unicatt.it
DOI 10.1002/ajmg.c.31326
Article rst published online in Wiley Online Library (wileyonlinelibrary.com): 12 April 2012

2012 Wiley Periodicals, Inc.

80%) [Fombonne, 1999; Chakrabarti

and Fombonne, 2005] and attention deficit 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 comprehend the patients presentation both
at the neuropsychological, developmental, and behavioral picture. In addition to
that, laboratory testing, to detect possible genetic and metabolic alterations, is
also a relevant part of the diagnostic
work-up in ASD.
The purpose of this work is to briefly 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 GENETIC
EVALUATION
Once the neuropsychological diagnosis
of an ASD disorder is established, it
is crucial to proceed with a medical
examination in order to detect concomitant issues that require treatment. Among those, seizures, feeding
and gastrointestinal problems, sleep

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disturbances and dental abnormalities

[Olivie, 2012].
In addition, a clinical genetics evaluation 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 recommended 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 geneticist 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 dysmorphic 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

AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

family members. In spite of all these

recommendations not all ASD children
usually undergo a clinical genetic evaluation, but mainly those with evident
dysmorphic features, positive family history 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 phenotypes that can be related to ASD. For
instance, family history can be positive
for alcoholism, depression, manic-depression, obsessivecompulsive disorders, substance abuse, seizures, anxiety
disorders, Tourrette-like motor tics, anorexia. 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 spectrum 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 recurrence 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 syndrome, Rett syndrome, tuberous sclerosis, Angelman syndrome, SmithLemli
Opitz syndrome and others. This recognition is crucial to drive appropriate
molecular testing.
On the other hand, the general
practice of testing all ASD patients for
FMR1 mutations without a proper clinical 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 towards one gene or another.

105

GENETIC FACTORS
ASD is one of the most heritable neuropsychiatric disorders, with an increased recurrence risk (more than 20fold) in rst-degree relatives [Bayley
et al., 1995]. This observation points
to a major genetic contribution. However, despite signicant research, including high throughput technique
applications, efforts have failed to identify genes of large-effect, whose identication 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 relation to ASD [Betancur, 2011] and associated/overlapping phenotypes such
as intellectual disability, ADHD, epilepsy, 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 phenotype. Because of this wide genetic heterogeneity, 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 recognize the basic disorder and determine
proper molecular testing. Even an oligogenic inheritance of multiple hypomorphic 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 responsible for ASD can be classied
into three subgroups: cytogenetic alterations detectable on standard karyotype
(up to 5%), copy number variants
(CNVs), which can be found in a

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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

variable percentage of cases (between

10% and 35%), and single gene mutations (less than 5%) [Miles, 2011].
Abnormalities of the standard karyotype 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 duplication 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 syndromes, such as Down syndrome (up
to 7% of cases) and Turner syndrome,
as well as other sex chromosome disorders 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 signicant gene-content), polymorphic CNVs
(usually inherited, small and with poor
gene-content). A third category
includes CNVs of unknown clinical signicance (medium sized, with signicant gene-content, usually inherited
from a parent with a border-line phenotype). The most common ASD-related
CNVs are the 15q11-q13 duplication,
the 7q21 deletion, and the 16p11.2
microdeletion with its reciprocal microduplication [Weiss et al., 2008], but other ones are being recurrently reported.
All CNVs specically associated with
ASD are annotated in a dedicated database 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 variable phenotypes including autism,
atypical autism, schizophrenia, dyslexia,
intellectual disability, ADHD and
others, it is likely that these represent
predisposing genomic alterations leading to a variable nal phenotype correlated 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

ARTICLE

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 single gene disorders frequently associated
with ASD is reported in Table I.
With respect to fragile X syndrome,
both FMR1 full mutations and premutations can be found in children
with ASD: it is estimated that 13% of
ASD children may have alterations in the
FMR1 gene. This is not surprising considering the overlapping of the neurobehavioral phenotypes in ASD and
fragile X syndrome.
Rett syndrome is also frequently
associated with autism: MECP2 mutations are reported in approximately 1%
of children diagnosed with autism. On
the other hand, about 18% of girls ending up with a diagnosis of Rett 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
Fragile X
PTEN extreme macrocephaly
Rett syndrome
Tuberous sclerosis
Timothy syndrome
Phenylketonuria
Creatine biosynthesis and transport disorders

SmithLemliOpitz syndrome
Sotos syndrome
Moebius syndrome
Duchenne muscular dystrophy
PhelanMcDermid syndrome

Gene locus

% ASD among patients

FMR1
PTEN
MECP2
TSC1 and TSC2
CACNA1C and CACNA1F
PAH
SLC6A8
L-arginine:glycine amidinotransferase
Guanidinoacetate methyltransferase
7-Dehydrocholesterol reductase
NSD1
Unknown
Dystrophin
SHANK3

Up to 30%
n.a.
Up to 18%
50%
High
6%
Up to 80%

5080%
n.a.
30%
Up to 90%

ARTICLE

and extreme macrocephaly [Buxbaum

et al., 2007; Varga et al., 2009].
Another gene which is likely
to cause a recognizable syndromic autism, is SHANK3. Heterozygous mutations and intragenic deletions have been
reported in about 15% of patients with
ASD, epilepsy, tendency to overgrowth,
hypotonia, and absent language [Herbert, 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 without additional neurological issues
[Hass, 2010].
Phenylketonuria, adenylosuccinase lyase
deciency, creatine deciency syndromes usually show behavioral alterations overlapping with autistic
symptoms in addition to severe intellectual disability and seizures [Van den
Berghe et al., 1997; Baieli et al., 2003;
Newmeyer et al., 2007].
SmithLemliOpitz syndrome is probably the condition most frequently associated 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.,

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107

2011]; however, none of these mutations

has led to a clinically distinguishable
phenotype.

All these factors need to be considered when collecting anamnestic data in

ASD children.

ENVIRONMENTAL
FACTORS

MOLECULAR DIAGNOSIS
AND TESTING STRATEGIES

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 epidemiologic 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 increased risk for ASD [Palac and
Meador, 2011]; maternal alcohol consumption 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 capability 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 include advanced paternal age (risk increased 2.2 times with paternal age
>50) [Hultman et al., 2011], oxidative
stress and environmental pollutants (such
as air pollution, organophosphates, and
heavy metals).
Epilepsy, food intolerance, immune
and hormonal dysfunction, mitochondrial and metabolic unbalance (i.e., low
glutathione, low antioxidant and detoxicant 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 represent concomitant medical problems
[Herbert, 2010].

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 (metabolic) cause in each ASD patient. Even with
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 specic genetic syndrome is suspected,
or the patient has morphological alterations 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, although a genetic basis is possible, no

specic test for monogenic ASD should
be recommended because the possibility

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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)

of identifying a pathogenic mutation is

negligible. Only array-CGH testing is
worthwhile because there is a 10%
chance of identifying a possibly pathogenic CNV [Sebat et al., 2007]. Standard
karyotype is the rst step when arrayCGH 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 arrayCGH. 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 be mentioned that the results of
array-CGH are not always easy to interpret: for instance, the same CNVs 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 experienced medical geneticists.
Not infrequently, array-CGH in
ASD patients detects CNVs commonly
associated with specic microdeletion or microduplication syndromes:
among those, the 22q11 deletion (associated with DiGeorge velo-cardio-facial

syndrome), the 17p11 deletion (associated with SmithMagenis syndrome),

the 22q13 deletion (associated with PhelanMcDermid 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 eventually propose autism-specic-gene sequencing, when such diagnostic tools
will become available and affordable.
Fragile X testing is frequently recommended as a rst step molecular test
in ASD. However, in cohorts not
screened by clinical evaluation the diagnostic 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,

Figure 1.

ARTICLE

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, including language, social, or other psychiatric 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 unknown etiology has a lower recurrence
risk (between 1% and 2%) [Miles, 2011].

Proposed genetic diagnostic itinerary for autism spectrum disorders.

ARTICLE

The medical geneticist is often required to make predictions about the

clinical outcome in case a genetic alteration 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 spectrum is highly variable to the point
that people with autism may be particularly talented in many professional settings, including scientic laboratory
[Mottron, 2011]. However early diagnosis 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 resolution array-CGH, exome and full genome 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 hundreds 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.

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