The ASHA Leader - February 2015 - 28

OVERHEARD

On the Genetic Trail of Hearing Loss
Genetic testing can help identify the underlying causes and management of hearing loss. Sami
Amr, a clinical molecular geneticist, led a recent Web chat touching on related complexities and
challenges, including cost, ethics and interpretation. The Leader listened in.
Deborah hayes: Can you please suggest
the information that clinicians, including
audiologists and otolaryngologists, can
provide that will be helpful in interpreting
genetic test results?
sami amr: There are several websites,
such the Online Mendelian Inheritance
in Man (OMIM) and GeneReviews, that
provide information on the gene/disease
associations and particular variants within
genes that can help explain the relationship
between particular variants and genes to
hearing loss-whether it be syndromic or
nonsyndromic.
However, one of the difficulties of
interpretation is assessing novel variants
seen in individuals-and most variants will
be unique to a family or an individual-
and, therefore, we need to dig deeper to
find out how any particular variant may be
related to the hearing loss. To do this, we
use a number of pieces of evidence, such
as the clinical picture (does it match with
the type/severity/onset) of hearing loss
associated with a gene; gene- and proteinspecific information, such as domains that
are intolerant to variation as well as the
pathogenic variant spectrum in that gene;
and the frequency of the variant in normal
individuals and in affected individuals.
And this requires a collaborative effort
from the clinic and the lab; part of my job,
as a clinical molecular geneticist, is to work
with clinicians and audiologists to make
sense of genetic findings in the context of
the clinical manifestations seen in hearing
loss patients.
ellen mastman: Are there ever
mutations during growth and development
in an organism after it is born (or hatched)
that may affect development later on?
amr: Yes, there are scenarios where this
is possible in genetics; however, this is less
common in the hearing loss world. We refer
to a mutation that occurs after an organism
is born as a somatic mutation; this type of
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FEBRuARY 2015 |

THE ASHA LE ADER

mutation begins with a single cell in the
body and increases as that cell replicates.
However, our bodies have a way to identify
these mutations during DNA replication
and "fix" or eliminate them. But when
the DNA-editing machinery doesn't work
or is overwhelmed, those cells begin to
replicate and may behave erratically, which
would eventually cause tumor growth or
metastasis.
VaibhaVi Dharkar: How can different
testing facilities share their data? Are there
any data banks that are collecting this
information?
amr: Yes, absolutely. There are several
initiatives for data sharing from a variety
of sources: research, clinical, molecular
laboratories. One such effort that our
lab is involved in is the ClinVar database,
a publically available database that
encourages different labs to submit their
variants and their variant classifications (for
example, are these variants pathogenic or
benign), and what clinical features are seen
in the individuals that have these variants.
In addition, this particular database
provides a rating for the variant
classification. For example, if a variant was
only seen and classified once, it would
get a one-star rating. But if it was seen in
multiple clinical diagnostics laboratories
that all agree on its classification, it may
receive a two- or three-star rating, to reflect
a higher confidence in the community on
this classification.
There are other databases, such as
dbSNP, Exome Variant Server and many
disease-specific databases out there as
well. While these databases are useful
to tell you if a variant was seen in the
general population or in other individuals
with hearing loss, you have to be careful
when using these databases because the
classification system or assessment process
for variants in other databases may not be
as reliable as in ClinVar.

one of the main ethical
or controversial issues
is related to the return
of results. For example,
if a patient comes in for
hearing loss testing, and
we identify a mutation
that does not address
the hearing loss but
is associated with a
different disease, do we
return that information
to the patient? this is
compounded if this
disease is something
untreatable.
tina Posch: As genetic testing becomes
more affordable and clinically beneficial,
what controversies or ethical dilemmas do
you foresee down the road?
amr: Good question and an important
issue that people in the clinical genetics
field are trying to address. One of the main
ethical or controversial issues is related
to the return of results. For example, if a
patient comes in for hearing loss testing,
and we identify a mutation that does not
address the hearing loss but is associated
with a different disease, do we return
that information to the patient? This is
compounded if this disease is something
untreatable.
The argument is that some people do
not want to know if they will develop
Huntington's disease because there is no
cure for it or treatment. On the other hand,
if we do identify mutations for a disease
that can be managed or treated, which

The ASHA Leader - February 2015

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