Transcript Genetics of Hemophilia

Genetics of Hemophilia:
The Role of Genetic Testing and the
Use of Genetics to Guide Treatment
Anna Chalmers, MD
Rush University Medical Center, Chicago, Illinois
A REPORT FROM THE 65TH ANNUAL MEETING OF THE NATIONAL HEMOPHILIA FOUNDATION (NHF 2013)
AND THE 55TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY (ASH 2013)
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The Genetic Basis of Hemophilia

Hemophilia is a hereditary disease caused by
deficiencies in coagulation factors VIII (hemophilia
A) and IX (hemophilia B) due to mutations of the F8
and F9 genes on the X chromosome.

Deletion and insertion mutations and mutations that
cause premature termination of synthesis usually
cause severe disease. Certain missense mutations
also can lead to severe hemophilia.

More commonly, missense mutations cause mild or
moderate disease; in fact, 90% of patients who have
mild-to-moderate hemophilia A have missense
mutations. The majority of patients with hemophilia
B also have missense mutations.
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Who Should Have Genetic Testing

The Medical and Scientific Advisory Committee for
the National Hemophilia Foundation recommends
that all hemophilia patients have genotype testing;
an initiative is underway to create a comprehensive
de-identified database of these mutations.

Appropriate family members can also undergo
genetic testing to determine carrier status.

In pretesting counseling, only about 30% of cases of
hemophilia are sporadic; despite this finding, most
carriers are unaware of their status and will require
supportive counseling.
National Hemophilia Foundation Web site. MASAC recommendations on the NHF Genotyping Project for
persons with hemophilia. November 1, 2009; Pruthi RK. Mayo Clin Proc. 2005;80:1485
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Who Should Have Genetic Testing

In testing possible
carriers, it is best to
target a known
mutation.

If the mutation is
unknown, then the
approach is similar
to testing patients with hemophilia: first screen for
an intron 22 inversion mutation, as it is the most
common overall cause of unspecified hemophilia.

If this test is negative, then screen the whole gene.
Pruthi RK. Mayo Clin Proc. 2005;80:1485
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Who Should Have Genetic Testing

Carrier status affects preconception counseling.

It is important to discuss family planning options,
including preimplantation genetic testing, with
carriers.

Patients who are carriers and are pregnant with male
fetuses need to be followed by a multidisciplinary
team of specialists throughout the pregnancy to
address any possible perinatal testing and ensure a
safe delivery.
National Hemophilia Foundation Web site. MASAC recommendations on the NHF Genotyping Project for
persons with hemophilia; November 1, 2009
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5
Using Genetics to Guide Treatment

A small percentage of hemophilia patients with
severe disease, as defined by coagulation factor level,
have a milder-than-expected clinical presentation;
this observation has generated interest is using
genetic information to help guide management
decisions.

Carcao and coworkers examined 621 previously
untreated patients and classified them according to
whether they carried null or non-null mutations.

Patients with null mutations experienced their first
hemarthrosis at a younger age, but the difference
was only 2 months.
Santagostino E et al. J Thromb Haemost. 2010;8:737; Carcao MD et al. Blood. 2013;121:3946
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Using Genetics to Guide Treatment

Most patients with an inhibitor phenotype have large
alterations, such as large deletions, nonsense
mutations, or frameshift mutations, in F8 or F9.

A small percentage of patients with this phenotype
can develop anaphylaxis to replacement factor, a lifethreatening, difficult-to-manage clinical situation.
» Eight patients with hemophilia B who had experienced
anaphylaxis to FIX were genotyped and compared to
patients with severe disease; those who had complete gene
deletions were at the highest risk of developing anaphylaxis.
» Patients with major gene mutations who are at high risk of
anaphylaxis may need to be infused in the supervised clinic
setting instead of receiving treatment at home.
Thorland EC et al. Haemophilia. 1999;5:101
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