cardiovascular genetics
TRANSCRIPT
Cardiovascular Genetics
Dr. Md.Toufiqur Rahman MBBS, FCPS, MD, FACC, FESC, FRCPE, FSCAI,
FAPSC, FAPSIC, FAHA, FCCP, FRCPG
Associate Professor of CardiologyNational Institute of Cardiovascular Diseases,
Sher-e-Bangla Nagar, Dhaka-1207
Consultant, Medinova, Malibagh branchHonorary Consultant, Apollo Hospitals, Dhaka and
STS Life Care Centre, Dhanmondi [email protected]
CRT 2014Washington DC, USA
Mendelian disordersMendelian CVDs include HCM, LQTS, Marfan syndrome, and familial DCM. These
diseases are characterized by a clear mode of inheritance and one or a few genes causing the disease, with mutations within the genes s howing strong association with the disease and marked phenotypic effects.
Genetic testing of the affected individual is often indicated in these Mendelian CV genetic diseases, not for d iagnostic purposes (diagnosis is usually a clinical diagnosis), but for facilitating genetic testing and screening in at risk family members.
When performing genetic testing in most Mendelian CV genetic diseases, the best approach is usually to perform a full screen of all available genetic variants in the index case, and then perform focused testing of only that g enetic variant in at risk family members.
Marfan syndrome is a connective tissue disorder inherited in an autosomal dominant fashion, with 95% of cases caused by mutations in the fibrillin 1 extracellular matrix protein gene (FBN1), and predisposes to aortic aneurysms and dissections.
Familial DCM and HCMFamilial DCM is a heterogeneous genetic disease, with variable prese
ntations, reduced penetrance, and differentmodes of inheritance. It is caused by mutations in 33 known genes, but these account for only 30 35% of cases;thus, the role of genetic testing is unclear.
Familial HCM is a relatively common genetic disease showing an autosomal dominant mode of inheritancecaused by mutations in 1 of 14 genes encoding components of the sarcomere, with genetic testing identifying oneof these mutations in 50 75% of cases. Thus, genetic testing can be useful in helping to confirm a diagnosis andfor guiding screening in at risk family members.
Familial HCM needs to be differentiated from LV hypertrophy resulting from other genetic disorders such as Fabrydisease, amyl-oidosis, or other metabolic cardiomyopathies, especially in younger individuals.
Long QT syndrome
LQTS is typically autosomal dominant but with variable penetrance, and is subdivided into 12 types based on theunderlying causative gene.
Genetic testing will identify a known LQTS mutation in approximately 75% of cases,
and thus, can help with diagnosis and for guiding screening in at risk family members.
Genetics of Coagulation and bleedingFactor V Leiden is a genetic variant that causes APC
resistance and is the most common genetic cause of VTE,causing up to 50% of cases.
It is transmitted in an autosomal dominant fashion, and genetic testing for thisgenetic variant is indicated in certain patients with a VTE.
Warfarin metabolism is determined partially by genetic variants in two genes, the hepatic cytochrome p450
enzyme CYP2C9 and VKORC1, which explain 30 40% of the total variation in final warfarin dose.
Genetic testingfor these variants may help with achieving optimal warfarin doses more quickly, and for improving outcomes.
Genetics of Clopidogrel resistance
Clopidogrel activation is mediated partially through a hepatic cytochrome p450 enzyme coded by the gene,CYP2C19, and variants in this gene have been associated with reduced platelet inhibition and worse clinicaloutcomes in patients treated with clopidogrel.
The ACCF and AHA suggest testing for these CYP2C19 variantsmay be indicated for patients treated with clopidogrel who are at moderate or high risk for CV events.
MiscellaneousCommon CVDs such as CAD, MI, and atrial
fibrillation demonstrate a more complex model of genetic risk; thus,genetic testing is not currently routinely indicated in these diseases.
Novel genomic technologies including epigenetics, copy number variation testing, and DNA resequencing willhopefully help refine the genetic architecture of these common CVDs and facilitate creation of a robust risk prediction model. [email protected]
