Brugada Syndrome
Brugada syndrome, caused by an ion channelopathy, is characterized by STsegment abnormalities in leads V1-V3 on ECG and an increased risk of sudden
death in patients with structurally normal hearts. Brugada syndrome manifests
predominantly during adulthood, in patients between ages 20 to 40.
Symptoms include ventricular arrhythmia, syncope, and cardiac arrest usuallyduring sleep or rest. In some patients sudden cardiac death may occur without any
sign of clinical symptoms. Brugada syndrome may overlap with conduction disease.
Symptoms such as first-degree AV block, intraventricular conduction delay, rightbundle branch block, and sick sinus syndrome could be included in a differentialdiagnosis.
The prevalence of Brugada syndrome is estimated to affect 5 in 10,000 people
worldwide. Although Brugada syndrome affects both men and women, the condition
is more prevalent among men.
Brugada syndrome is inherited in an autosomal dominant manner.

Indications for genetic testing:
1.
2.
3.
4.
5.

Confirmation of clinical diagnosis
Risk assessment of at-risk relatives
Prenatal diagnosis for known familial mutation
Differential diagnosis of Brugada syndrome from other genetic heart
conditions
Genetic counseling

Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is characterized by high LDL (low densitylipoprotein)cholesterol level that cause atherosclerotic plaque deposition in thecoronary arteries, increasing the risk for early cardiovascular disease and stroke.
Deposition of cholesterol is also found in the tendons of the hands, elbows, knees
and feet (xanthomas) and around the eyes (xanthelasmas).
Heterozygous FH is associated with heterozygous pathogenic variant in one ofthree genes – LDLR, APOB, PCSK9, and occurs at a frequency of about 1:500.
Homozygous FH is much rarer, occurring in about 1:1,000,000 in general
population. Homozygous FH results from biallelic mutations in one of the following
genes: LDLR, LDLRAP1, APOB, PCSK9.

Indications for genetic testing:
1.
2.
3.

Confirmation of clinical diagnosis
Carrier testing for known familial mutations
Genetic counseling

Long QT Syndrome
Long QT Syndrome (LQTS) is a rare hereditary disease that is characterized by ap r o l o n g e d Q T- i n t e r v a l o n t h e e l e c t r o c a r d i o g r a m ( E C G ) d u e t odelayed repolarization of the heart. Affected individuals have an increased risk forventricular tachycardia with syncope or even sudden death due to ventricularfibrillation.
The estimated prevalence of LQTS is one in 2000. The clinical symptoms of LQTS
are quite variable depending on the causative mutation, age, gender, environmental
factors and therapeutic interventions. The age of onset is usually younger than 40
years of age, however, the condition can occur as early as in infancy. The diagnosis
and risk assessment of LQTS is based on patient’s clinical symptoms, including
ECG findings, as well as family history. However, the diagnosis of LQTS can bechallenging since around 2.5% of the healthy population have prolonged QTinterval while some of LQTS patients do not exhibit abnormal ECG findings.
Therefore, genetic testing is a valuable component in the assessment of LQTS
patients.
LQTS is caused by mutations in genes encoding for the subunits of various ionchannels. To date, over 600 disease causing mutations have been recognized in atleast 15 genes. It has been shown that mutations in known LQTS related genes
can be detected in more than 75% of patients with clinical diagnosis. Most
commonly the mutations are detected in KCNQ1 (LQT1), KCNH2 (LQT2)and SCN5A (LQT3) genes and account for about 95% of mutations in affectedindividuals. The disorder is inherited as an autosomal dominant trait, although arare subtype with autosomal recessive inheritance has been reported (Jervell andLange-Nielsen Syndrome).

Indications for genetic testing:
1.
2.
3.
4.
5.

Confirmation of clinical diagnosis
Distinguishing different forms of LQTS to direct appropriate therapies
Testing of family members of the affected individuals
Carrier status detection of known mutation
Genetic counselingMarfan Syndrome and Related Disorders
Marfan syndrome is a systemic disorder of connective tissue with multiple organsystems involvement. The main manifestations include ocular, skeletal, andcardiovascular systems. The syndrome may also affect lungs, skin, and dural sacsurrounding the spinal cord. Cardiovascular manifestations typically include
dilatation of the aorta, mitral valve prolapse, and enlargement of the proximal
pulmonary artery.
Marfan syndrome is inherited in an autosomal dominant manner, caused
by mutations in the FBN1 gene. Mutations in the FBN1 gene have also been
associated with MASS syndrome (myopia, mitral valve prolapse, borderline andnon-progressive aortic enlargement, and nonspecific skin and skeletal features),mitral valve prolapse syndrome, ectopia lentis syndrome, ShprintzenGoldberg syndrome, and Loeys-Dietz syndrome.
Marfan syndrome shares overlapping phenotypic features with other syndromes
including congenital contractural arachnodactyly (CCA), familial thoracic aortic
aneurysms and aortic dissection (TAAD),Ehlers-Danlos syndrome (EDS), andhomocystinuria.

Indications for genetic testing:
1.
2.
3.
4.
5.

Confirmation of clinical diagnosis
Differential diagnostics between Marfan syndrome and genetically/
phenotypically related disorders
Predictive testing for at-risk asymptomatic family members
Prenatal diagnosis for known familial mutation
Genetic counseling

Noonan SyndromeNoonan syndrome is an autosomal dominantly inherited disease characterized byshort stature, congenital heart defect and delayed mental development of varyingdegree. Patients with Noonan syndrome also have a characteristic appearance:
short neck, cervical skin fold, low set ears, hypertelorism. Additionally lymphatic
system dysplasia may occur, which is the basis of cystic hygroma and occipital foldenlargement in the fetus.
The incidence of Noonan syndrome is about 1:1000-2500. Noonan syndrome isgenetically heterogeneous. In 50% of patients mutations occur in the PTPN11gene. 10% of cases are associated with mutations in the SOS1 gene, 3% in theRAF1 gene and 1% in the KRAS gene.
Indications for genetic testing:
1.
2.
3.
4.

Confirmation of clinical diagnosis
Parental testing in case of a causative mutation has been identified in an
affected individual
Genetic counseling
Prenatal diagnosis

Statin-Induced Myopathy
Statins inhibit the synthesis of cholesterol and promote the production of low
density lipoprotein (LDL)-binding receptors in the liver resulting in an unusuallymarked decrease in the level of LDL, and a modest increase in the level of highdensity lipoprotein (HDL) circulating in blood plasma. Therefore, statin drugs are
the primary pharmacologic treatment for hypercholesterolemia and coronary
artery disease worldwide.
Despite their demonstrated safety and efficacy, 25% to 50% of individuals withcardiovascular disease are nonadherent with statin medications after one year.
Although there may be multiple contributing factors, many experts report that acontributor to statin nonadherence is associated with side effects, including skeletal
muscle toxicity due to poor or compromised metabolism of statin drugs.
Statin-induced myopathy has been associated with SLCO1B1 gene variant
NM_006446.4:c.521T>C (rs4149056). The risk of myopathy may be substantially
increased in patients who take 80 mg ofsimvastatin daily, as well as in those whoare also receiving certain other drugs.
Indications for genetic testing:1.
2.

Risk assessment for developing statin-induced myopathy
Optimizing the statin dose

Venous Thrombosis
The annual incidence of venous thrombosis ranges from approximately 1 to 3 per1000 people. Venous thrombosis events often occur when multiple risk factors,including genetic and environmental, are present simultaneously. Acquired risk
factors of venous thrombosis are age, immobilization, surgery, trauma, malignancy,
myeloproliferative disorders, obesity, pregnancy, postpartum period, hormone
replacement therapy or use of oral contraceptives. Genetic risk factors are related
to a 30- to 80-fold higher risk for developing a thrombotic episode.
Indications for genetic testing:
1.
2.
3.
4.
5.
6.

Vein thrombosis before the age of 50
Recurrent vein thrombosis in family
Identified genetic variant for higher risk of venous thrombosis in family
For women in addition to the above named:
Myocardial infarction in 50-year-old women who are smoking
Vein thrombosis in the period of taking oral contraceptives
The presence of pregnancy complications, for example multiple miscarriages,
preeclampsia and stillbirth.