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Autism spectrum disorders & the clinical geneticist: an approach to the family: the geneticist does not make the diagnosis of an ASD. Rather, this specialist is part of the interdisciplinary team of professionals who are involved in the diagnosis and management of such individuals. Ideally, a referral is made to the geneticist after the diagnosis has been made.


More than any other condition, the autism spectrum disorders (ASDs) affect families. Although these conditions have profound effects on the individual with the disorder, they also significantly alter the lives of parents, siblings, the family, and the community. This extended nature has significance to the geneticist, the specialist whose role is to identify the cause of inherited conditions and provide counseling to the patient and family. To the geneticist, ASDs are a symptom complex in which difficulties in socialization and communication occur in association with stereotypic behaviors. This symptom complex is a "final common pathway," the result that multiple causes have on the brain. The goal of a genetic evaluation in an individual with ASD is to:

(1) identify an underlying cause so families can learn more about the individual's likely future functioning and potential associated medical problems,

(2) provide genetic counseling, which will inform the family about the likely recurrence risk of an ASD in future progeny, and

(3) provide an explanation of "why this happened."

For these reasons, evaluation by a geneticist should be offered to all individuals diagnosed with ASD.

The fact that genetic factors play a role in the etiology of most cases of ASD is supported by multiple lines of evidence. For instance, according to the CDC, in 2012, the prevalence of autism at age eight in six areas of the United States was approximately 1 in 88 (MMWR, March 30, 2012 / 161;3; 1-19). However, after the birth of a child with an ASD, the empiric recurrence risk (based on observation of thousands of families) for full siblings is between 4% and 7%. Further, if a second child has autism, the recurrence risk rises to 25% to 35%. These increases point to the role genetic factors play in the etiology of ASD.

The geneticist does not make the diagnosis of an ASD. Rather, this specialist is part of the interdisciplinary team of professionals who are involved in the diagnosis and management of such individuals. Ideally, a referral is made to the geneticist after the diagnosis has been made.


What can a family expect when their child is referred for genetic evaluation? In most cases, the evaluation begins with a complete history, focusing on issues that might have contributed to the affected individual's condition. Although, as previously stated, genetic factors play a role in most cases of ASD, in some cases, environmental exposures occurring prior to birth have also been implicated. For instance, the geneticist is concerned about exposure to intrauterine infections such as Rubella or cytomegalovirus, prenatal exposure to drugs and chemicals, such as Valproic Acid, an anti-seizure medication, and alcohol. Information about the individual's general health, age at onset of symptoms, presence of language and developmental regression and of seizures, and the age at which the diagnosis was made is also obtained.

Next, a complete family history is taken. Information about at least three generations is recorded. The family history includes details about the presence of ASDs, as well as other developmental and behavioral disabilities. Also recorded is information about any genetic disorder, miscarriages and childhood deaths in related individuals.

This is followed by a complete physical exam. During the exam, the geneticist searches for clues that suggest the presence of a genetic disorder (a partial list appears in Table 1). For instance, does the individual have pigmented spots on the skin that are a clue to the diagnosis of neurofibromatosis, or hypopigmented spots in the shape of ash leaves, which suggest tuberous sclerosis? Are there unusual facial features such as a prominent forehead or jaw, or large ears that point to fragile X syndrome? Is the head larger (suggesting conditions associated with a mutation in a gene called PTEN) or smaller than would be expected for a child of that age? Does the proband have unusual hand movements such as flapping (associated with fragile X), or ataxic, puppet-like movements (seen in Angelman syndrome)?
Table 1. Partial list of "common" genetic syndromes
associated with autism

SYNDROME                         GENE OR CHROM INVOLVED /
                                     ETIOLOGY / TEST

Angelman syndrome            UBE3 / absence of maternal copy
                             / FISH, methylation

CHARGE syndrome              CHD7 / mutation / direct DNA

Down syndrome                Trisomy 21 / nondisjunction /
                             chromosome analysis

Fragile X syndrome           FMR-1 / Trinucleotide (CGG)
                             expansion / Direct DNA

Neurofibromatosis            NF1/ mutation / direct DNA

Prader-Willi syndrome        SNRPN / absence of paternal
                             copy / FISH, methylation

PTEN associated disorders    PTEN / mutation / direct DNA
(Cowden syndrome,

Rett syndrome                MECP2 / mutation, deletion /
                             Direct DNA analysis

Smith-Lemli-Opitz synd       DHCR7 / mutation / Direct DNA

Sotos syndrome               NSD1 / mutation / direct DNA

Tuberous sclerosis           TSC1 (20%), TSC2 (60%) /
                             mutations / direct DNA

Velo-Cardio-Facial syndrome  deletion 22q11.2 / deletion /
(aka diGeorge, Shprintzen)   FISH

Williams syndrome            deletion 7q11.23 / deletion of
                             26 genes / FISH

Adapted from Schaefer GB and Mendelsohn NJ. Genetics
evaluation for the etiologic diagnosis of autism
spectrum disorders. 2008; Genet Med 2008;10:4 -12.


Following completion of the history and physical exam, an assessment is made about the likely cause of the child's condition. Specifically, the geneticist must decide whether the child has a primary ASD (an ASD not associated with an underlying genetic disorder or environmental teratogen), or an ASD that is secondary to another cause (for instance, a prenatal exposure, such as congenital rubella syndrome or fetal alcohol spectrum disorder, or the presence of a genetic disorder, such as neurofibromatosis, fragile X or Rett syndrome). Approximately 80 will be judged to have a primary ASD, while 20% will have a secondary ASD.

Based on the outcome of the assessment, the geneticist will decide the laboratory tests, if any, that should be performed. As noted in Table 2 (and described in Schaefer GB, Mendelsohn NJ. Genetics evaluation for the etiologic diagnosis of ASDs. Genet Med 2008;10:4-12.), the testing should be done in stages or tiers, in which tests are ordered in sequence, based on results of previous evaluations.

Table 2. Template for the clinical genetic diagnostic evaluation of ASDs

Pre-evaluation: Before referral to the geneticist, the following should be accomplished:

1) Confirmation of diagnosis of ASD by trained professional (using objective criteria)

2) Cognitive testing

3) Sensory screening (complete audiogram)

4) If clinical suspicion of seizures/regression: Electroencephalogram

Evaluation: Following referral, pt should have:

1) History

2) Pedigree including information on at least three generations

3) Physical Exam with special attention to dysmorphic features (should include Woods lamp evaluation for hypopigmented macules)

4) Assessment: Using information from above, decide if patient has ASD as part of a genetic syndrome or as the result of exposure to a teratogen (secondary ASD) or is an isolated finding (primary ASD).

Work-up: Dependent on results of assessment:

1) If ASD is secondary, and specific diagnosis is suspected, proceed with targeted testing:

a) Rubella titers--if clinical indicators present

b) DNA analysis is single gene disorder is suspected (see Table1); also family members should be examined to determine if they have similar features

c) High resolution chromosome analysis is chromosomal anomaly is suspected.

2) If ASD is primary, proceed with tier one of generalized work-up:

Tier 1 Work Up should include:

a) Metabolic screening--check newborn screen results; serum lactate and pyruvate. If normal, no need to continue; if abnormal, proceed to tier 2.

b) Microarray comparative genomic hybridization (array CGH)

c) DNA for Fragile X

d) DNA for MECP2 associated disorder (Rett syndrome) in female.

e) PTEN gene testing (if head circumference is 2.5 SD greater than the mean)

Tier 2 Work Up:

a) If metabolic screen abnormal, complete metabolic work-up (serum and/or urine amino acids, organic acids, mucopolysaccharides)

b) array CGH of parents if copy number variant identified.

c) Appropriate DNA testing for first degree relatives (if mutation is found)

Tier 3 Work-Up

a) Brain magnetic resonance imaging

b) Serum and urine uric acid

c) If elevated, Hypoxanthine-guanine phosphoribosyl transferase (HgPRT) and Phosphoribosylpyrophosphate (PRPP) synthetase superactivity testing

d) If low, purine/pyrimidine panel (uracil excretion, xanthine, hypoxanthine)

Adapted from Schaefer GB and Mendelsohn NJ. Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. 2008; Genet Med 2008;10:4-12.

If an ASD is suspected to be due to an underlying genetic disorder, such as fragile X syndrome, direct DNA testing should be performed. If a congenital infection is suspected, testing the blood for antibodies may be helpful. Syndromes caused by prenatal exposure to specific drugs or chemicals do not require confirmatory testing; confirmation of the diagnosis is based instead on the history of the exposure and the presence of characteristic physical features.

However, the number of children with an ASD that is secondary to a genetic or environmental condition is small. As already noted, the majority will have primary ASD, with no features suggestive of an accompanying genetic disorder. It is this population that presents the greatest challenge to the geneticist. In these cases, discovering information that will prove helpful to the family is often difficult and elusive. However, newly developed genetic tools have offered hope that the cause will be identified in more individuals with a primary ASD. And additional tools that are currently on the horizon offer even more hope.

"Silent" inborn errors of metabolism, problems with the way an infant or child's body is able to handle normal metabolites, have been postulated to be a cause of primary ASDs. In 1994, Laszlo et al. reported that 43% of children who met the DSM III criteria for ASD had elevated levels of lactic acid, a non-specific biochemical marker of underlying abnormalities in glucose metabolism (Laszlo A, Horvath E, et al.: Serum serotonin, lactate and pyruvate levels in infantile autistic children. Clinica Chimicta Acta 1994; 229:205-207). Although subsequent studies have identified a smaller percentage of probands with elevated lactate levels, routine testing for lactate and pyruvate should be part of first tier testing. If levels are normal, no further evaluation is indication; if abnormal, a series of tier 2 tests should be performed.

The need for analysis of chromosomes has been well established in the evaluation of the cause of an ASD. Numerous small deletions and duplications, called copy number variants (CNVs), have been associated with ASDs. The most common of these is a duplication of a small portion of chromosome 15 (15q11.2); this is seen in 3% of cases of ASDs; in addition, a small deletion in the short arm of chromosome 16 (16p11.2), has been seen in 1%. In the past, the approach to identify these errors has always included high resolution chromosome analysis accompanied by fluorescent in situ hybridization (FISH) looking for errors at the end of the chromosomes (sub-telomeres). However, more recently, microarray comparative genomic hybridization ("array CGH" for short), a powerful technique much more sensitive at identifying CNVs, has supplanted these previously used techniques. Studies have indicated that using array CGH, CNVs can be identified in 10% of individuals with sporadic autism beyond what would be identified by standard chromosomal testing (Bejjani BA, Shaffer LG: Clinical Utility of Contemporary Molecular Cytogenetics. Annual Review of Genomics and Human Genetics 2008, 9:71-86).

Although array CGH has the potential to identify CNVs, the technique cannot identify mutations within genes. As such, even in the absence of clinical features that suggest the diagnosis, because of the high yield in this population and the implications to other members of the family, all children with an ASD should have DNA testing for fragile X, and all females should be tested for MECP2 associated disorder (MECP2 mutations are associated with Rett syndrome).

According to Schaefer and Mendelsohn, the aggregate result of tier 1 testing is that between 22% and 33% of individuals with primary ASD would have an identifiable cause of their condition. This includes between 10 with CNVs, 5% with fragile X, 2% to 3% with MECP2-related disorders, and 5% to 10% with other causes.

Based on results received, following this first tier, a second tier of testing should be performed. As noted in Table 2, if the results of metabolic testing are abnormal, a more complete evaluation is needed to pinpoint the specific error in metabolism. If a CNV or genetic mutation is identified in the proband, the parents should be tested to see if this is inherited or occurred de novo (spontaneously).

Finally, depending on the results of the tier 2 testing, a group of tests in the third tier might be performed. This includes the performance of an MRI to identify an underlying structural brain anomaly, more complete metabolic testing, and, as indicated, DNA testing of additional members of the proband's family.

In the near future, whole exome sequencing (WES) and whole genome sequencing (WGS) will become available as clinical tools. As noted above, although array CGH will identify subtle duplications and deletions of the DNA, this test is not able to detect changes within the genes. Currently, direct DNA testing can only be performed for a relatively small number of genes; the beauty of WES and WGS is that these techniques will enable us to check all 22,000 to 23,000 genes that compose the human genome. Although the technology currently exists, the cost of performing these tests are still too high to permit their use in the routine clinical setting. However, the cost is dropping and within a few years, the availability of these tests will revolutionize the way that children with ASDs are evaluated.


Following completion of this work-up, the family is invited back for genetic counseling.

* If a specific etiology, such as fragile X, has been identified, counseling is provided for that condition.

* If the child with primary autism was found to have a genetic cause for his condition, such as a CNV that is not present in either parent, a low recurrence risk, on the order of 1%, can be cited.

* If the work-up has failed to reveal any enetic cause, an empiric recurrence risk for full siblings of 4% to 6% can be cited.

* If the next child is female, the risk of her developing an ASD is on the lower side.

* If the next child is male, the risk is on the higher side.

* If it has been found that two children in the family are affected, the empiric recurrence risk rises to between 25% to 35%. This visit is also an opportunity for the family to ask questions of the geneticist.

Follow-up with the geneticist is necessary, especially when no underlying etiology has been identified. Because technology in the field of clinical genetics is advancing so rapidly, it is possible that new tests will become available that will identify an etiology in children in whom currently no etiology is identifiable. For this reason, periodic reavaluation on an annual or biannual basis is important.


Director, Children's Evaluation and Rehabilitation Center, Rose F. Kennedy University Center for Excellence in Developmental Disabilities, Albert Einstein College of Medicine


Robert W. Marion, M.D. is director, Children's Evaluation and Rehabilitation Center, Rose F. Kennedy University Center for Excellence in Developmental Disabilities, Albert Einstein College of Medicine. He is chief, Genetics and Developmental Medicine, Department of Pediatrics, Einstein and Montefiore Medical Center
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Author:Marion, Robert W.
Publication:The Exceptional Parent
Geographic Code:1USA
Date:Apr 1, 2013
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