FM SEPTEMBER 2018 ISSUE - digital edition

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Genetics testing and inherited heart diseases
Professional bodies now recommend genetic testing for the management of
patients with genetic disease as well as at-risk members in the family
DR HISHAM AHAMED
The last few decades have led
to the identification of the
genetic basis of a large number of
cardiovascular diseases. They include
dilated cardiomyopathy (DCM) and
hypertrophic cardiomyopathy (HCM)
with mutations related to the sarcomere
and structural genes, channelopathies
with mutations in ion channel genes,
arrhythmogenic cardiomyopathy with
mutations in desmosomal genes
and aortopathies with mutations in
genes encoding for connective tissue
elements. As a result, genetic testing
has taken on an important role in
managing families with the inherited
cardiovascular disease. Various
professional bodies have now included
the recommendation of genetic testing
for the management of patients with
the disease as well as at-risk members
in the family.
Why genetic testing in CVD?
1. Diagnostic genetic testing : This can
be performed to establish a specific
genetic diagnosis. For example, the
clinical phenotype may be shared
among different disease entities, each
with their own underlying cause,
prognosis and treatment. In patients
with left ventricular hypertrophy, genetic
testing will help in characterizing it as
sarcomeric HCM or an HCM phenocopy.
2. Predictive Genetic Testing : This is
done in apparently healthy relatives
to determine who has inherited the
causal variant in the family and is at
risk for developing the disease. The
majority of inherited cardiovascular
diseases exhibit autosomal dominant
inheritance pattern, with a 50 %
chance of transmission to the offspring.
This makes an evaluation of at risk
Condition
Hypertrophic
cardiomyopathy
Dilated cardiomyopathy
Arrhythmogenic
cardiomyopathy
Long QT syndrome
Catecholaminergic
polymorphic ventricular
tachycardia
Major Genes or Gene
Families Analyzed
Detection
rate
Diagnostic
Criterion
Effect on
Proband
Management
Sarcomere gene 30 to >60 NA + Yes
Sarcomere and
cytoskeleton genes
(including TTN)
30-40 NA NA Yes
LMNA 90 Yes ++ Yes
Loeys-Dietz syndrome
Familial thoracic
aortic aneurysms and
dissections
Vascular Ehlers Danlos
syndrome
Familial
hypercholesterolemia
TGFBRl/2, SMAD3, and
TGFB2/3
ACTA2, MYH11, and
MYLK
70-90 Yes ++ Yes
20-25 NA ++ Yes
COL3A1 ~95 Yes ++ Yes
LDLR, APOB, PCSK9,
and LDLRAP1
healthy family members an important
strategy. The aim of phenotypic and
genotypic family evaluations are to
identify individuals with the previously
unrecognized disease and currently
healthy family members who are at risk
for future disease development.
When to perform genetic testing?
All patients diagnosed with an inherited
Detection rates and clinical utility of diagnostic genetic testing
for selected inherited cardiovascular diseases
60-80 Yes ++ Yes
Predictive
Genetic
Testing
from over 2,800 individuals from over 260 distinct South
Asian groups. We identified 81 unique groups, 14 of which
had estimated census sizes of more than 1 million, that
descend from founder events,” says Dr K Thangaraj, Senior
Principal Scientist at Centre for Cellular and Molecular Biology,
Hyderabad, who led this large study in 2016.
Less medical attention
Even as the criticality of inherited heart diseases in India
is becoming more and more apparent, the local medical
community is yet to pay the required attention to the issue.
“There are multiple challenges here. While the first and the
most important issue is the low awareness about inherited
heart diseases, the other two are the cost and practical
The mutations
for different
cardiomyopathies have
been identified and
cataloging of mutations
on a phenotypic basis
is underway.
Dr. Shailesh Pande
Senior Medical Geneticist,
Metropolis
20 / FUTURE MEDICINE / SEPTEMBER 2018