Gregor Mendel (1822-1884) had a strict definition of genes: pieces of biologic information
that assort and segregate independently and code for discrete physical traits. The
frequencies of normal and abnormal manifestations could be predicted mathematically.
His insights still form the basis of genetic science, but it has become much more
complex. When considering genetic evaluation of a patient, it is helpful to understand
the utility of modern genetic testing technologies.
A karyotype remains the best confirmatory test for Down syndrome and Turner syndrome. A chromosome microarray analysis is useful for known conditions such as 22q11.2 deletion syndrome and as a first-line
test for developmental disabilities and multiple congenital anomalies. If the diagnosis
is clinically obvious and the genetics straightforward, directed mutation testing or single gene sequencing still is the best approach; it is relatively inexpensive with short turn-around time.
Fragile X syndrome, spinal muscular atrophy and many common Mendelian conditions can
be tested this way.
Increasingly, there are syndrome families rather than individual conditions. A “family”
of syndromes comprises those that overlap phenotypically and whose genes may code
for interacting proteins. Recognizing that a patient has a diagnosis within a syndrome
family (e.g., Marfan-like or Noonan-like) allows tailored testing, even if the specific
diagnosis is not definable clinically.
A helpful advance has been next generation (NextGen) sequencing technology so that many genes can be tested at once. “Gene panel” tests may reduce
testing time, cost and blood draws. Gene panels are useful when a patient’s phenotype
is clearly within a syndrome family but not specific enough for diagnosis. Conversely,
a single phenotype (e.g., Noonan syndrome) may result from mutation in a number of
genes, which can be panel tested. There also are panels for diagnosis categories (e.g.,
The broadest gene panel is whole exome sequencing (WES or “an exome”). This evaluates exons and significant intronic sequences of protein-coding
genes, roughly 20,000 of our 25,000 genes, accounting for 2% of the genome. A pared
down “medical exome” comprises genes with known pathology. WES is available for clinical
testing and is common in genetic research programs. WES results identify a confirmed
pathologic variant about 25% of the time.
WES testing is useful when the patient’s phenotype and family history suggest a single-gene
disorder without clear diagnosis. Sometimes, it is more cost-effective than gene panels.
WES is not useful for the triplet-repeat expansion conditions (fragile X, myotonic
dystrophy, etc.), and it will not identify gene deletions or duplications. WES can
have sequence gaps and may not identify all clinically significant variants, even
if they are present.
Whole genome sequencing (WGS or “a genome”) is the broadest test based on current technology. WGS is not limited
to protein-coding genes. WGS will find deletions and duplications, covers genes more
uniformly, and has better analysis of gene regulatory regions. It is more expensive
and the results much more complicated. At this time, WGS is a research test, and its
commercial availability is limited.
2 facts about genetic testing
First, there is no “normal” in genetics. There is no baseline human genome. Genetic
results are unambiguous only when definitively abnormal. The studied gene(s) may be
mutated in a way the test is not designed to see, there may be a mutation in an untested
or unidentified gene, or a defined variant may not yet be recognized as pathologic.
DNA sequencing technology outpaces our understanding of sequence variants. Test results
are, by consensus agreement, reported in five categories: pathogenic, likely pathogenic,
variant of uncertain significance, likely benign and benign. Laboratories rely on
databases, conservation of the sequence across species, biochemical impact, and computer
and statistical analysis to assign the result. Pathogenic and likely pathogenic usually
are diagnostic; however, clinical correlation is necessary. Confirmation of diagnosis
may require parental testing. Benign and likely benign are reassuring.
Variants of uncertain significance are the most likely result of any sequencing test.
Data are insufficient to identify the variants as benign or pathogenic. In practice,
these are more frustrating than a negative result. Further evaluation of the variants
depends on the diagnostic situation.
Second, genetic testing results have implications beyond an individual patient’s diagnosis.
An abnormal result may inadvertently diagnose other family members. It may change
someone’s reproductive risk. Most genetic tests have low but real potential for unintended
consequences, including revealing non-paternity and unidentified (or unreported) consanguinity.
WES and WGS testing will find variants that may require other counseling and management.
It is a practice standard that laboratories report medically actionable results if
found (genetic cancers, Marfan syndrome, cardiomyopathies, etc.), regardless of whether
they were the reason for testing.
The more involved the testing, the greater the need for pre-test discussion with the
patient and family. WES and WGS require pre-test counseling and informed consent on
par with research testing. Genetic testing is expensive and is not covered universally
by insurance. Pretest insurance authorization and patient counseling regarding out-of-pocket
costs are important.
There is no “all in one” test and, as in all medicine, some tests are useful and appropriate
while others are not. Consultation with a genetic counselor or geneticist is recommended
to determine what genetic testing would be most helpful in the management of your
Dr. Scheuerle is a member of the AAP Council on Genetics Executive Committee and professor
in genetics and metabolism at the University of Texas Southwestern Medical Center,