by Angela E. Scheuerle, M.D., FACMG, FAAP
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
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., seizures).
The broadest gene panel is whole exome sequenc-
ing (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 avail-
able 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 pheno-
type and family history suggest a single-gene disor-
der 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 iden-
tify 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 un-
derstanding of sequence variants. Test results are,
by consensus agreement, reported in five categories:
pathogenic, likely pathogenic, variant of uncertain
significance, likely benign and benign. Laborato-
ries rely on databases, conservation of the sequence
across species, biochemical impact, and computer
and statistical analysis to assign the result. Pathogen-
ic and likely pathogenic usually are diagnostic; how-
ever, 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)
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
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 patient.
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, Dallas.
areas of guidance and support.
This research seems to be a call to action for career
Training programs and professional societies
alike must work together to fill this gap, focusing
on the priorities identified by trainees themselves.
Professional societies such as the Academy can play
a vital role by providing resources directly to train-
ees, having long been involved in augmenting their
members’ career development through education,
research and networking opportunities. The Section
on Critical Care plans to address the gap in men-
toring through programming at the 2017 National
Conference & Exhibition.
Additionally, professional societies can provide
resources to training programs aimed at graduate
medical education program leadership, such as the
Association of Pediatric Program Directors Leadership in Educational Academic Development and the
Association of Medical School Pediatric Department
Chairs Pediatric Leadership Development Program.
Though most PCCM trainees receive good to
excellent career guidance in fellowship, many op-
portunities for improvement remain. Partnerships
between training programs and professional societies
likely will be needed to help fellows pursue their
ideal career track, which is imperative to optimize
the workforce in all areas of pediatric critical care.
Dr. Riley is chair of the
AAP Section on Critical
Care Subcommittee on
Member Engagement and
Mentorship. Dr. Cifra is
a member of the subcommittee’s Mentorship Development Work Group
Dr. Riley Dr. Cifra
Critical care continued from page 12
Which genetic test is best for your patient?