Right Drug, Right Dose Through Personalized Medicine

The ACTA2 gene provides instructions for making a protein called smooth muscle alpha (α)-2 actin, which is part of the actin protein family. Actin proteins are important for cell movement and the tensing (contraction) of muscles. Smooth muscle α-2 actin is found in smooth muscle cells. Smooth muscle α-2 actin contributes to the ability of these muscles to contract, which allows the arteries to maintain their shape instead of stretching out as blood is pumped through them. More than 30 ACTA2 gene mutations have been identified in people with familial thoracic aortic aneurysm and dissection (familial TAAD). This disorder involves problems with the aorta. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can cause life-threatening internal bleeding.

ACTC1 encodes cardiac muscle alpha actin. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle contraction and generation of force to support the pump function of the heart

ApoBs are proteins found in lipoprotein particles that are artery-clogging. The apoB-containing lipoprotein particles that are the most damaging to our arteries include not only LDL cholesterol but also remnants of chylomicrons and VLDL (very low density lipoproteins). All three – LDL, VLDL, and chylomicrons – promote atherosclerosis-Atherosclerosis is a disease caused in large part by the build-up of excess cholesterol within the artery wall, which leads to cholesterol-rich deposits called plaque. When a plaque bursts or ruptures, blood clots form. They’re dangerous because they can block blood flow to vital organs like the heart and brain.

The CACNA1S gene provides instructions for making the main piece (subunit) of a structure called a calcium channel. Channels containing the CACNA1S protein are found in muscles used for movement (skeletal muscles). These skeletal muscle calcium channels play a key role in a process called excitation-contraction coupling, by which electrical signals (excitation) trigger muscle tensing (contraction).

COL3A1 There are more than 500 mutations in the COL3A1 gene have been found to cause a form of Ehlers-Danlos syndrome (EDS) called the vascular type. Ehlers-Danlos syndrome is a group of disorders that affect the connective tissues that support the skin, bones, blood vessels, and many other organs and tissues. Some rare types of EDS are characterized by cardiovascular problems – the vascular type carries a risk of arterial rupture at a young age, and in cardiac-valvular EDS there are severe progressive problems of the aortic and mitral valves.

The DSC2 gene provides instructions for making a protein called desmocollin-2. This protein is found in many tissues, although it appears to be particularly important in the heart muscle and skin. Desmocollin-2 is a major component of specialized structures called desmosomes. These structures help hold neighboring cells together, which provides strength and stability to tissues. Defects in DSC2 cause arrhythmogenic right ventricular dysplasia type 10, and susceptibility to cardiomyopathy.

Mutations in the FBN1 gene, which provides instructions for making a protein called fibrillin- Marfan syndrome is inherited in an autosomal dominant pattern. At least 25% of cases are due to a new ( de novo ) mutation. Treatment is based on the signs and symptoms in each person. Marfan syndrome is a disorder of the connective tissue. Connective tissue provides strength and flexibility to structures throughout the body such as bones, ligaments, muscles, walls of blood vessels, and heart valves.

GLA Currently, specific mutations are associated with the cardiac variant showing myocardial hypertrophy that is clinically similar to HCM. Patients with FD are at risk for developing cerebrovascular disease (CVD), cardiac sudden death, and renal failure, and these patients can benefit from specific treatments.

TPM1 (Tropomyosin 1) is a Protein Coding gene. Diseases associated with TPM1 include Cardiomyopathy, Familial Hypertrophic, 3 and Cardiomyopathy, Dilated, 1E. Among its related pathways are Cardiac conduction and Dilated cardiomyopathy (DCM).

TNNT2 Cardiac muscle troponin T is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration

TNN13 Approximately 10 mutations in the TNNI3 gene have been found to cause familial restrictive cardiomyopathy, which is characterized by stiffening of the heart muscle. Most of these mutations change single amino acids in the cardiac troponin I protein, which impairs the protein's function

TMEM43 This gene belongs to the TMEM43 family. Defects in this gene are the cause of familial arrhythmogenic right ventricular dysplasia type 5 (ARVD5), also known as arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5). Arrhythmogenic right ventricular dysplasia is an inherited disorder, often involving both ventricles, and is characterized by ventricular tachycardia, heart failure, sudden cardiac death, and fibrofatty replacement of cardiomyocytes. This gene contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC

TGFBR2 At least nine TGFBR2 gene mutations have been identified in people with familial thoracic aortic aneurysm and dissection (familial TAAD). This disorder involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can cause life-threatening internal bleeding.

SMAD3 Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3.

SCN5A A few mutations in the SCN5A gene have been found to cause progressive familial heart block. This condition alters the normal beating of the heart and can lead to fainting (syncope) or sudden cardiac arrest and death. The SCN5A gene mutations change single amino acids in the SCN5A protein.

The RYR2 gene provides instructions for making a protein called ryanodine receptor 2. This protein is part of a family of ryanodine receptors, which form channels that transport positively charged calcium atoms (calcium ions) within cells. For the heart to beat normally, the cardiac muscle must tense (contract) and relax in a coordinated way. This cycle of muscle contraction and relaxation results from the precise control of calcium ions within myocytes. In response to certain signals, the RYR2 channel releases calcium ions from the sarcoplasmic reticulum into the surrounding cell fluid (the cytoplasm). The resulting increase in calcium ion concentration triggers the cardiac muscle to contract, which pumps blood out of the heart. Calcium ions are then transported back into the sarcoplasmic reticulum, and the cardiac muscle relaxes. In this way, the release and reuptake of calcium ions in myocytes produces a regular heart rhythm. Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia. Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years.

The RYR-1 gene provides instructions for production of the RYR-1 receptor. The RYR-1 receptor is a channel in the sarcoplasmic reticulum in skeletal muscle cells that regulates the flow of calcium, a critical component of muscle contraction. Mutations in the RYR-1 gene have also been associated with susceptibility to malignant hyperthermia (MH), a severe and potentially fatal reaction to certain types of anesthesia (sedating or paralyzing drugs given by a doctor for medical/surgical procedures). Anyone with an RYR-1 gene mutation should take “malignant hyperthermia precautions” if anesthesia is required for a medical/surgical procedure. In addition, there are case reports of “wake MH”–i.e. an episode of MH that is unrelated to the administration of anesthesia. The PRKAG2 gene

The PRKAG2 gene provides instructions for making one part (the gamma-2 subunit) of a larger enzyme called AMP-activated protein kinase (AMPK). This enzyme helps sense and respond to energy demands within cells. It is active in many different tissues, including heart (cardiac) muscle and muscles used for movement (skeletal muscles). The enzyme may also regulate the activity of certain ion channels in the heart. These channels, which transport positively charged atoms (ions) into and out of heart muscle cells, play critical roles in maintaining the heart's normal rhythm.

The PKP2 gene provides instructions for making a protein called plakophilin 2. This protein is found primarily in cells of the myocardium, which is the muscular wall of the heart. Within these cells, plakophilin 2 is one of several proteins that make up structures called desmosomes. These structures form junctions that attach cells to one another. Desmosomes provide strength to the myocardium and are involved in signaling between neighboring cells.

The PCSK9 gene provides instructions for making a protein that helps regulate the amount of cholesterol in the bloodstream. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals. The PCSK9 protein controls the number of low-density lipoprotein receptors, (LDL) which are proteins on the surface of cells. These receptors play a critical role in regulating blood cholesterol levels.

The MUTYH (MYH) gene provides instructions for making an enzyme called MYH glycosylase, which is involved in the repair of DNA. This enzyme corrects particular errors that are made when DNA is copied (DNA replication) in preparation for cell division.

The MYBPC3 gene provides instructions for making cardiac myosin binding protein C (cardiac MyBP-C), which is found in heart (cardiac) muscle cells. In these cells, cardiac MyBP-C is associated with a structure called the sarcomere, which is the basic unit of muscle contraction. Sarcomeres are made up of thick and thin filaments. The overlapping thick and thin filaments attach to each other and release, which allows the filaments to move relative to one another so that muscles can contract. Regular contractions of cardiac muscle pump blood to the rest of the body.

Mutations in the LMNA gene, which encodes the two major lamin A and C isoforms, cause a diverse range of diseases, called laminopathies, including dilated cardiomyopathy, associated with a poor prognosis and high rate of sudden death due to conduction defect and early ventricular arrhythmia.

The LDLR gene provides instructions for making a protein called the low-density lipoprotein receptor. This receptor binds to particles called low-density lipoproteins (LDLs), which are the primary carriers of cholesterol in the blood. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals. Low-density lipoprotein receptors play a critical role in regulating the amount of cholesterol in the blood.. The number of low-density lipoprotein receptors on the surface of liver cells determines how quickly cholesterol is removed from the bloodstream.

KCNQ1 gene mutations increases the risk of an abnormal heart rhythm that can cause syncope or sudden death. The KCNQ1 gene mutations associated with short QT syndrome change single amino acids in the KCNQ1 protein. The mutations alter the function of ion channels made with the KCNQ1 protein, increasing the channels' activity.

Mutations in the KCNH2 gene can cause Romano-Ward syndrome, which is the most common form of a heart condition called long QT syndrome. Mutations in this gene account for approximately 25 percent of cases of Romano-Ward syndrome. Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death.

The ACTA2 gene provides instructions for making a protein called smooth muscle alpha (α)-2 actin, which is part of the actin protein family. Actin proteins are important for cell movement and the tensing (contraction) of muscles. Smooth muscle α-2 actin is found in smooth muscle cells. Smooth muscle α-2 actin contributes to the ability of these muscles to contract, which allows the arteries to maintain their shape instead of stretching out as blood is pumped through them. More than 30 ACTA2 gene mutations have been identified in people with familial thoracic aortic aneurysm and dissection (familial TAAD). This disorder involves problems with the aorta. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can cause life-threatening internal bleeding.

ACTC1 encodes cardiac muscle alpha actin. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle contraction and generation of force to support the pump function of the heart

ApoBs are proteins found in lipoprotein particles that are artery-clogging. The apoB-containing lipoprotein particles that are the most damaging to our arteries include not only LDL cholesterol but also remnants of chylomicrons and VLDL (very low density lipoproteins). All three – LDL, VLDL, and chylomicrons – promote atherosclerosis-Atherosclerosis is a disease caused in large part by the build-up of excess cholesterol within the artery wall, which leads to cholesterol-rich deposits called plaque. When a plaque bursts or ruptures, blood clots form. They’re dangerous because they can block blood flow to vital organs like the heart and brain.

The CACNA1S gene provides instructions for making the main piece (subunit) of a structure called a calcium channel. Channels containing the CACNA1S protein are found in muscles used for movement (skeletal muscles). These skeletal muscle calcium channels play a key role in a process called excitation-contraction coupling, by which electrical signals (excitation) trigger muscle tensing (contraction).

COL3A1 There are more than 500 mutations in the COL3A1 gene have been found to cause a form of Ehlers-Danlos syndrome (EDS) called the vascular type. Ehlers-Danlos syndrome is a group of disorders that affect the connective tissues that support the skin, bones, blood vessels, and many other organs and tissues. Some rare types of EDS are characterized by cardiovascular problems – the vascular type carries a risk of arterial rupture at a young age, and in cardiac-valvular EDS there are severe progressive problems of the aortic and mitral valves.

The DSC2 gene provides instructions for making a protein called desmocollin-2. This protein is found in many tissues, although it appears to be particularly important in the heart muscle and skin. Desmocollin-2 is a major component of specialized structures called desmosomes. These structures help hold neighboring cells together, which provides strength and stability to tissues. Defects in DSC2 cause arrhythmogenic right ventricular dysplasia type 10, and susceptibility to cardiomyopathy.

Mutations in the FBN1 gene, which provides instructions for making a protein called fibrillin- Marfan syndrome is inherited in an autosomal dominant pattern. At least 25% of cases are due to a new ( de novo ) mutation. Treatment is based on the signs and symptoms in each person. Marfan syndrome is a disorder of the connective tissue. Connective tissue provides strength and flexibility to structures throughout the body such as bones, ligaments, muscles, walls of blood vessels, and heart valves.

GLA Currently, specific mutations are associated with the cardiac variant showing myocardial hypertrophy that is clinically similar to HCM. Patients with FD are at risk for developing cerebrovascular disease (CVD), cardiac sudden death, and renal failure, and these patients can benefit from specific treatments.

TPM1 (Tropomyosin 1) is a Protein Coding gene. Diseases associated with TPM1 include Cardiomyopathy, Familial Hypertrophic, 3 and Cardiomyopathy, Dilated, 1E. Among its related pathways are Cardiac conduction and Dilated cardiomyopathy (DCM).

TNNT2 Cardiac muscle troponin T is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration

TNN13 Approximately 10 mutations in the TNNI3 gene have been found to cause familial restrictive cardiomyopathy, which is characterized by stiffening of the heart muscle. Most of these mutations change single amino acids in the cardiac troponin I protein, which impairs the protein's function

TMEM43 This gene belongs to the TMEM43 family. Defects in this gene are the cause of familial arrhythmogenic right ventricular dysplasia type 5 (ARVD5), also known as arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5). Arrhythmogenic right ventricular dysplasia is an inherited disorder, often involving both ventricles, and is characterized by ventricular tachycardia, heart failure, sudden cardiac death, and fibrofatty replacement of cardiomyocytes. This gene contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC

TGFBR2 At least nine TGFBR2 gene mutations have been identified in people with familial thoracic aortic aneurysm and dissection (familial TAAD). This disorder involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can cause life-threatening internal bleeding.

SMAD3 Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3.

SCN5A A few mutations in the SCN5A gene have been found to cause progressive familial heart block. This condition alters the normal beating of the heart and can lead to fainting (syncope) or sudden cardiac arrest and death. The SCN5A gene mutations change single amino acids in the SCN5A protein.

The RYR2 gene provides instructions for making a protein called ryanodine receptor 2. This protein is part of a family of ryanodine receptors, which form channels that transport positively charged calcium atoms (calcium ions) within cells. For the heart to beat normally, the cardiac muscle must tense (contract) and relax in a coordinated way. This cycle of muscle contraction and relaxation results from the precise control of calcium ions within myocytes. In response to certain signals, the RYR2 channel releases calcium ions from the sarcoplasmic reticulum into the surrounding cell fluid (the cytoplasm). The resulting increase in calcium ion concentration triggers the cardiac muscle to contract, which pumps blood out of the heart. Calcium ions are then transported back into the sarcoplasmic reticulum, and the cardiac muscle relaxes. In this way, the release and reuptake of calcium ions in myocytes produces a regular heart rhythm. Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia. Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years.

The RYR-1 gene provides instructions for production of the RYR-1 receptor. The RYR-1 receptor is a channel in the sarcoplasmic reticulum in skeletal muscle cells that regulates the flow of calcium, a critical component of muscle contraction. Mutations in the RYR-1 gene have also been associated with susceptibility to malignant hyperthermia (MH), a severe and potentially fatal reaction to certain types of anesthesia (sedating or paralyzing drugs given by a doctor for medical/surgical procedures). Anyone with an RYR-1 gene mutation should take “malignant hyperthermia precautions” if anesthesia is required for a medical/surgical procedure. In addition, there are case reports of “wake MH”–i.e. an episode of MH that is unrelated to the administration of anesthesia. The PRKAG2 gene

The PRKAG2 gene provides instructions for making one part (the gamma-2 subunit) of a larger enzyme called AMP-activated protein kinase (AMPK). This enzyme helps sense and respond to energy demands within cells. It is active in many different tissues, including heart (cardiac) muscle and muscles used for movement (skeletal muscles). The enzyme may also regulate the activity of certain ion channels in the heart. These channels, which transport positively charged atoms (ions) into and out of heart muscle cells, play critical roles in maintaining the heart's normal rhythm.

The PKP2 gene provides instructions for making a protein called plakophilin 2. This protein is found primarily in cells of the myocardium, which is the muscular wall of the heart. Within these cells, plakophilin 2 is one of several proteins that make up structures called desmosomes. These structures form junctions that attach cells to one another. Desmosomes provide strength to the myocardium and are involved in signaling between neighboring cells.

The PCSK9 gene provides instructions for making a protein that helps regulate the amount of cholesterol in the bloodstream. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals. The PCSK9 protein controls the number of low-density lipoprotein receptors, (LDL) which are proteins on the surface of cells. These receptors play a critical role in regulating blood cholesterol levels.

The MUTYH (MYH) gene provides instructions for making an enzyme called MYH glycosylase, which is involved in the repair of DNA. This enzyme corrects particular errors that are made when DNA is copied (DNA replication) in preparation for cell division.

The MYBPC3 gene provides instructions for making cardiac myosin binding protein C (cardiac MyBP-C), which is found in heart (cardiac) muscle cells. In these cells, cardiac MyBP-C is associated with a structure called the sarcomere, which is the basic unit of muscle contraction. Sarcomeres are made up of thick and thin filaments. The overlapping thick and thin filaments attach to each other and release, which allows the filaments to move relative to one another so that muscles can contract. Regular contractions of cardiac muscle pump blood to the rest of the body.

Mutations in the LMNA gene, which encodes the two major lamin A and C isoforms, cause a diverse range of diseases, called laminopathies, including dilated cardiomyopathy, associated with a poor prognosis and high rate of sudden death due to conduction defect and early ventricular arrhythmia.

The LDLR gene provides instructions for making a protein called the low-density lipoprotein receptor. This receptor binds to particles called low-density lipoproteins (LDLs), which are the primary carriers of cholesterol in the blood. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals. Low-density lipoprotein receptors play a critical role in regulating the amount of cholesterol in the blood.. The number of low-density lipoprotein receptors on the surface of liver cells determines how quickly cholesterol is removed from the bloodstream.

KCNQ1 gene mutations increases the risk of an abnormal heart rhythm that can cause syncope or sudden death. The KCNQ1 gene mutations associated with short QT syndrome change single amino acids in the KCNQ1 protein. The mutations alter the function of ion channels made with the KCNQ1 protein, increasing the channels' activity.

Mutations in the KCNH2 gene can cause Romano-Ward syndrome, which is the most common form of a heart condition called long QT syndrome. Mutations in this gene account for approximately 25 percent of cases of Romano-Ward syndrome. Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death.