TRAINING and EDUCATION
genetic testing have implications beyond the individual
patient. “Female carriers of hemophilia can have normal
clotting factor plasma levels, and in that case, the only
way to identify them would be through genetic testing,”
explained Dr. Swystun.
Testing typically finds a disease-causing mutation in
up to 98 percent of patients with hemophilia A and up
to 99 percent of those with hemophilia B. 3 A gene can be
rendered dysfunctional by many types of mutations, so
tests must do more than identify which gene is mutated.
Accordingly, there are a variety of genetic tests than can
be performed in patients with bleeding disorders. For
most patients with hemophilia A or B, mutations are
found in the coding regions of the gene, so that’s where
scientists start.
In patients with severe hemophilia A, Dr. Swystun
said she usually will first look for inversions – a literal flip
or abnormal positioning of the DNA – in introns 1 and
22, which are the most frequently observed mutations
in this disease. Inversion analysis can be performed by
several different methods of polymerase chain reaction
(PCR) or Southern blot analysis. Of the more than 2,000
unique mutations associated with hemophilia A that
have been catalogued in genetic databases, most involve
point mutations (66.5%), followed by deletions (23%) and
duplications (4.8%). These mutations most often occur in
the A domains of FVIII. 4
More than 1,000 unique mutations have been identi-
fied for hemophilia B, and these are present throughout
the FIX gene, including the promoter region and the 3’
untranslated region. Like hemophilia A, the majority of
FIX variants are point muta-
tions (73%), followed by dele-
tions (16.3%) and insertions
(3.3%); however, no inver-
sions have been identified.
Mutation analysis typically
involves direct sequencing
of coding and regulatory
regions, although scientists
will perform copy number
variant (CNV) analysis to
determine whether a patient
has deletions or duplications
of certain genes.
Each testing method carries its own advantages
and limitations. Southern blot analysis, for example, is
labor-intensive and uses hazardous radiochemicals. PCR
can provide results rapidly, but poor amplification of the
sample DNA and other errors can produce false-negative
and false-positive results.
“Genetic testing results can be
very revealing, but we know that
genetic testing is still an imperfect
and rapidly evolving science.”
Unknowns and Inhibitors
And there’s still more to learn, Dr. Swystun said. “There is
a small percentage of patients in whom we could sequence
everything – their exons, their intron-exon boundaries,
the promoter – and we could perform CNV analysis and
inversion testing, but we still won’t find out why they have
the disorder.”
For these patients, she noted, scientists are exploring
newer strategies, like next-generation sequencing, to
reveal other variants within deep introns that are causing
—STEFANIE DUGAN, MS, CGC
the disease. “This is still an emerging area for molecular
diagnostics,” Dr. Swystun said, adding that “it is impor-
tant in helping us understand what’s happening with the
patient as well as the underlying genetics of the disorder.”
Alternatively, if a patient’s symptoms are severe, a
genetic test may help to determine his or her risk of
developing inhibitors to certain treatments, explained
Bhavya Doshi, MD, a hematologist at the Children’s
Hospital of Philadelphia.
Existing treatments for hemophilia or vWD generally
help replenish whichever clotting factor a patient is lack-
ing or provide a substitute that performs a similar func-
tion to the missing factor. Depending on the severity of
the disease, these treatments may be given regularly as a
preventive measure or saved for use only in the event of
a bleed. The development of antibodies against factors,
however, is a common complication of treatment;
HEMATOLOGY / ONCOLOGY
Honolulu, Hawaii
The Hawaii Permanente Medical Group, Inc. is seeking a BC/ BE Hematologist/ Oncologist to join its Oncology Department
at the Kaiser Permanente Moanalua Medical Center, located 5 miles from downtown Honolulu.
POSITION HIGHLIGHTS
• Exceptional opportunity for a Hematologist/
Oncologist with solid clinical skills to practice all
facets of hematology and oncology in an innovative,
collaborative and fully integrated
health system
• 6 Oncologists, 1 Gynecologic Oncologist,
2 Oncology Physician Assistants
• Shared call responsibilities
• Multiple clinical trials
POSITION QUALIFICATIONS
• BC/BE in Oncology and Hematology
• Experience preferred, but not required
Hawaii Permanente Medical Group is the state’s largest and most
experienced multi-specialty group comprised of over 600 providers
dedicated to providing the highest quality clinical care and building
lifetime relationships with peers and patients within Hawaii’s richly
diverse communities.
careers.hawaiipermanente.com
EXCELLENT BENEFIT PACKAGE
• Relocation Allowance
• Pension plus Profit-Sharing Plans
• Flexible Spending Plans
• Vacation and Paid Holidays
• Educational Leave and Allowance
• Comprehensive Medical and Dental Insurance
• Sick Leave and Disability Income Benefits
• Professional Liability Insurance
Many know Hawaii as an attractive tourist destination with
beautiful scenery, mild weather, friendly people, and a host of
cultural and recreational opportunities. These elements, and
others, make Hawaii an excellent place to live.
TO APPLY:
Send your Cover Letter and CV to:
Amy Akamine, Provider Recruiter
Email: A m y . R A . A k a m i n e @ k p . o r g
Phone: (808) 432-5679, press option 2
Fax: (808) 432-5827