Manual of Cardiovascular Medicine

I.INTRODUCTION. Genetic abnormalities have been associated with all types of cardiovascular disease, including coronary atherosclerosis, rhythm disorders, aortic disease, and structural heart disease. Since the initial descriptions of familial hyperlipidemia (FH) and the mutations in the low-density lipoprotein receptor (LDL-R), genetic studies have fostered an improved understanding of the underlying pathophysiology of various cardiovascular disease states. Furthermore, the sequencing of the human genome coupled with the advent of new DNA sequencing technologies has increased the expeditious pace of cardiovascular genomics. The ability to efficiently scour through the massive amount of genomic information is improving our understanding of the contributions of genetics to cardiovascular disease.

This understanding would potentially lead to an improved ability to accurately diagnose disease, prevent progression, and risk stratify at the individual level. Furthermore, this information will add to our understanding of the relationship between DNA variants and the response to drugs or other treatment modalities. The pharmacogenomic profiles developed may provide a refined approach to treatment with less toxicity. A more comprehensive assessment of future risk for both patient and potentially affected family members would also be feasible.

Although there are some examples within cardiovascular disease of simple monogenic disorders explained by principles of Mendelian inheritance, many of the entities, such as coronary atherosclerosis, acute myocardial infarction (MI), and atrial fibrillation (AF), are complex traits with multiple genes contributing to the phenotype. As opposed to Mendelian disorders, which are deterministic, complex traits are probabilistic.

It will require extensive time and effort to be able to define all the variations in all the genes that contribute to the susceptibility to or protection from a complex trait. Furthermore, the simple identification of genes involved does not address the issue of gene–gene and gene–environment interactions influencing complex traits. There have been extensive recent reports of genomic variants associated with risk of diseases. These variants are common, often accounting for 20% to 30% of the population attributable risk, but with an odds ratio of 1.2 or 1.3, for example, only 20% to 30% excess risk. These are common variants for common diseases. The hunt to find rare variants that induce susceptibility to common diseases with high risk (or protection) will be more challenging, but eminently feasible with sequencing technology and ultra high–throughput genotyping. At some point in the future, the major genomic underpinnings for most cardiovascular diseases will be known. Furthermore, the integration of all of the genomic variants for any cardiovascular disease has not been undertaken. What follows is a brief overview of what is known today about the genetic basis for a sampling of disease entities within cardiovascular medicine.

II.METHODOLOGY. The process of discovering relevant genetic underpinnings of generally complex traits requires an extensive analysis of genetic information in large populations. Complex traits without simple Mendelian patterns of inheritance are difficult to analyze, given that there are often multiple genes involved, with many gene interactions being important. However, even before attempting this task, perhaps the single most significant goal is to accurately and concisely define the phenotype in question. In addition, many variations often exist within a single category of cardiovascular disease such as hypertrophic cardiomyopathy (HCM) and acute MI. The ability to clearly define cases and controls is paramount to obtaining accurate and reproducible information.

Here are the major methods of identifying DNA variants associated with cardiovascular disease. Of note, some of the single nucleotide polymorphism (SNP) variants that have been found are not in a gene, but actually in areas of the genome not associated with gene expression. It is not yet known how these variants exert their effect. Of note, the major variants for MI (at 9p21) and AF (at 4q25) fall into this category of intergene (i.e., not in a gene).

A.Genome-wide association studies. Gene association studies utilize the concept that multiple SNPs, where a single nucleic acid substitution results in a different allele, can affect the risk of developing a disease in question. This is especially true in diseases of complex traits such as coronary artery disease (CAD) and MI. Using genes of interest in a particular disease phenotype, scans are conducted in areas of interest in both cases and controls to compare haplotype frequency to determine if a statistically significant difference between the two groups in the region of interest exists. One of the limitations of this technique is the inability to know whether the SNP of interest is involved in the pathogenesis or simply associated (in linkage disequilibrium) with another SNP that may actually be involved in the process. Utilizing this process of gene association across the entire genome is now possible with high-throughput sequencing technology of up to 1 million SNPs assessed per individual and the term “genome-wide” association has been coined. The SNPs assessed are tagging tiny bins of the genome, such that in a genome of an individual of European ancestry, there are only about 250,000 bins, most of which are sampled by current high–throughput genotyping. Each bin is typically inherited as a block (haplotype). The breakdown of the genome into bins via the International Haplotype map was critical in making current genome-wide association studies possible.

Target sequencing of genes at GWAS loci is now commonplace. Using this method the researcher has the opportunity to discover if rare genetic variants in the coding region of any of the genes in the loci may be related. In addition, the era of whole-genome sequencing has arrived. In whole-genome sequencing the complete DNA sequence of the individual’s genome can be determined. This includes both chromosomal and mitochondrial DNA. Today an entire genome can be sequenced for about $1,000. Also individual genes can be sequenced cheaply and quickly. These new technologies have increased the speed and lowered the cost of sequencing thereby increasing access to many more researchers and accelerating discovery.

B.Linkage analysis. Linkage analysis is another tool used to identify genes that are possibly involved in the pathogenesis of complex traits. The use of linkage analysis begins without any assumptions as to the potential involvement of various genes. It is based on the idea that during the process of meiosis when recombination events occur, they tend to involve loci on a particular chromosome that are closer together than farther apart. By following the inheritance of certain known loci, assumptions can be made about the presence of alleles that cosegregate with them. Using linkage analysis, the potential exists to identify these known loci as markers and determine the transmission through a pedigree and its relationship to the phenotype in question. In doing so, it may be possible to suggest that an allele in proximity to known loci may be associated with a particular phenotype. The logarithm of odds ratio (LOD score) is used to estimate the (distance) relationship between the known locus of interest and an unknown locus thought to be associated with the disease phenotype. A LOD score of 3 is used to classify such a statistically meaningful linkage.

C.Gene expression profiling. The identification of certain disease alleles or loci associated with disease-causing genes provides valuable information but remains limited in its scope. The statistical association of genes and disease does not prove causation or even involvement in disease. Gene expression profiling takes this concept one step forward in trying to delineate gene expression. The presence of transcription profiles may provide more useful information in terms of relevance of findings made in gene association studies or linkage analysis. Technology now permits the evaluation of large genomes in a rapid fashion to derive expression profiles, which can then be compared between diseased and healthy individuals to draw conclusions about which genes are transcriptionally active in certain phenotypes.

III.GENES INVOLVED IN INDIVIDUAL CARDIAC DISEASE PROCESSES

A.Coronary atherosclerosis and atherothrombosis. Coronary atherothrombosis and atherosclerosis remain significant causes of morbidity and mortality in the population as a whole. There is a great deal of variation in presentation in atherosclerosis and in acute MI. The presence of atherosclerosis is necessary but not sufficient for atherothrombosis. There are separate factors involved that predispose to plaque rupture and thrombosis. Even within the category of plaque rupture, the clinical phenotypes vary significantly, as reflected by the spectrum of diseases that constitute the acute coronary syndromes. These entities are complex traits and are influenced by multiple pathways. Inflammation, endothelial dysfunction, and dyslipidemias are only a few of the pathways influencing the development of atherothrombosis and atherosclerosis. Delineating the genetic basis of specific pathophysiological mechanisms, in most cases, is a work in progress, but it may help to broaden our understanding of the disease.

1.Dyslipidemia: FH and other genetic variants. Dyslipidemia is a known risk factor for the development of atherosclerosis. FH is a well-characterized, albeit relatively uncommon, entity defined by elevated levels of serum LDL levels, which predispose to coronary atherosclerosis. Often, these patients can develop atherosclerotic disease between 20 and 30 years of age. In FH, the dyslipidemia is often severe and not responsive to standard lifestyle and pharmacologic interventions.

a.Autosomal dominant hypercholesterolemia. Three genes are implicated in causing familial hypercholesterolemia (FH), the LDLR gene (LDL Receptor), the APOB gene (apolipoprotein B), and the PCSK9 gene (proprotein convertase subtilisin/kexin type 9). However, a genetic cause for approximately 20% of cases in known loci is unknown. Mutations in any one of these three genes can cause FH and they are inherited in an autosomal pattern.

(1)FH resulting from mutations in the LDLR gene is the most common form of FH. The LDLR gene is located at 19p13.2 and encodes for a protein known as a LDL-R. These receptors regulate the amount of cholesterol in the blood. There are approximately 1,700 mutations in the LDLR gene affecting many aspects of LDLR function such as reducing the number of LDL-R produced in the cells or interfering with the receptor when removing LDLs from the blood. Alterations in the gene range from point mutations to gene rearrangements. Homozygotes (two mutant alleles) and heterozygotes (one mutant allele) for FH vary in terms of the severity of lipid levels. The majority of individuals are heterozygous, and those with homozygous patterns of inheritance are more severely affected and are more likely to be diagnosed during childhood. Consanguinity increases the risk of homozygous inheritance and should be noted. Typically, these patients and affected family members develop premature coronary atherosclerosis and MI.

(2)The APOB gene is located at 2p32.3 and encodes for the production of two forms of the apolipoprotein B protein a component of lipoproteins, the apolipoprotein B-100 and the apolipoprotein B-48. The mutations in the apolipoprotein B-100 cause familial hypercholesterolemia. The cellular mechanisms involved in cholesterol metabolism are complex, and there are many potential targets where mutations can significantly affect phenotype. One such example is a point mutation in the apolipoprotein B (apo B) component of the LDL molecule. The Arg3500Gln (R3500Q) is the most common substitution in the apo B (APOB) gene and results in the inability of LDL to bind to its LDLR. This mutant allele is more common in Northern European populations as a cause of hyperlipidemia, but the phenotype appears to be less severe than in the FH caused by LDLR mutations. The R3500 W is another APOB gene mutation identified in East Asian populations as a common cause of FH. Mutations in the APOB gene occur in 5% to 10% of cases of FH with a country variation in incidence. In some countries such as Japan, Russia, Spain, and Finland the APOB genetic mutations have not been identified in FH cases.

(3)The PCSK9 gene, located at 1p32.3, is responsible for increasing degradation of the LDL receptor. Approximately 1% to 2% of FH involves the PCSK9 gene. Mutations in PCSK9, such as D129N, D374H, D374Y, E 32K, E670G, F216L, R215H, S127R, D374Y, and R496W, confer gain in function and cause FH. Loss-of-function PCSK9 mutations such as G236S and N3541 are fairly common and act to reduce serum cholesterol levels, thereby conferring a protection against coronary atherosclerosis. Therefore, loss-of-function mutations do not cause FH. Many new PCSK9 mutations have been identified, but their effect on PCSK9 functions and their role in FH in different populations requires further investigation.

(4)In 2016, in a large Icelandic study, 13 new rare or low frequency variants with large effects on lipid levels were discovered while 14 previously reported ones were confirmed. Five of these variants were identified within genes associated with CAD including the PCSK9 and the LDLR genes. One of the variants (rs200238879) identified in the LDLR gene was determined in a 1997 study as a cause of familial hypercholesterolemia in Iceland. These results indicate the complexity of the genetic picture for dyslipidemia and the power of whole-genome sequencing in detecting rare variants in large global samples.

(5)In addition to the FH syndromes, there is a multitude of genes involved in more frequently occurring types of dyslipidemia. Phenotypically, these forms of dyslipidemia are less severe and more amenable to treatment than those observed in the FH population.

b.Autosomal recessive hypercholesterolemia. Autosomal recessive hypercholesterolemia occurs as a result of mutations in the LDL-R adaptor protein 1 gene (LDLRAP1) at 1p36.11. More than 10 mutations are known to cause this condition. These mutations result in either the production of a nonfunctional version of the LDLRAP1 protein or do not make any protein. The phenotype of this form of FH is milder than the autosomal dominant form of the disease and more amenable to treatment with lipid-lowering agents.

2.Endothelial function. The MEF2a gene located at 15q26.3 encodes for a transcription factor protein involved in vascular development. MEF2A localizes to the endothelial cell of coronary arteries and is believed to be important in the function of endothelial cells. Mutations in this gene could be a cause of CAD autosomal 1 (ADCAD1). In 2003, a mutation in the MEF2a gene was described in a large family with autosomal dominant transmission of coronary atherothrombosis. A21-bp deletion in exon 11 was thought to result in loss of function. Additional variants in the MEF2A thought to be associated with MI and CAD have also been reported. T 21-bp deletion has not been conclusively found in any family apart from that in the original study. This particular mutation may be a “private mutation” for the family in the original study and therefore extremely difficult to replicate. There is much discussion about the role of the MEF2A and its rare variants and their genetic contributions in ADCAD1. Recent genome-wide association studies have failed to identify the MEF2A locus on chromosome 15q26 when detecting loci associated with CAD. To add to the debate, scientists point to mixed results linking MEF2A mutations to ADCAD1. In 2008, researchers did not find any evidence that the MEF2A gene had any linkage or association with MI/CAD in a large German study. In 2010, researchers found that mutations of exon 11 in MEF2A were not involved in sporadic CAD in a Chinese population. However, in 2013, mutations of MEF2A exon 12 were linked to Premature CAD in a Chinese population. In 2014, the mutation in exon 11 was identified in a Chinese population and it was reported that six or seven amino acid deletions and synonymous mutations (147143G→A) may be associated with CAD in this population. These inconsistent results highlight the need for further genetic studies to determine the role of MEF2A’s genetic component in ADCAD1.

3.Inflammation. The genes, ALOX5AP (arachidonate 5-lipoxygenase–activating protein) located at 13q12.3 and LTA4H (leukotriene A4 hydrolase) located at 12q22, encode proteins involved in the leukotriene pathway, particularly in the synthesis of the proinflammatory leukotriene B mediators.

a.In 2004, the case for inflammation as a significant participant in acute MI was made stronger by the discovery, through linkage analysis to a locus at 13q12-13, of a 4-SNP haplotype known as Hap A (SG13S25, SG13S114, SG13S89, and SG13S32) in the gene ALOX5AP. Carriers of the variant had higher levels of leukotriene B4. This variant was found to double the risk of MI and to almost double the risk of stroke. Another haplotype variant, Hap B (SG13S377, SG13S114, SG13S41, and SG13S35) of the ALOX5AP gene was found to confer a doubling of the risk of MI in a British cohort. In Italy, researchers identified an increased risk for CAD with Hap B only. In a large German study, presence of the haplotype B indicated an association with an increased risk of MI. These studies provide strong evidence of the role of ALOX5AP gene for increased CAD risk in Europeans. In a case–control study of a US Midwestern population with European American ancestry, seven SNPs in the ALOX5AP gene along with two haplotypes (Hap A and Hap B) were genotyped. The results indicated that Hap B and one of the SNPs (SG13S377) were significantly associated with increased risk of premature CAD. In a meta-analysis conducted in 2010, the Hap B and SNP (rs1722842) variants in the ALOX5AP gene were associated with coronary heart disease, whereas Hap A was associated with the risk of MI. However, lack of correlation between ALOX5AP gene variants and CAD, and ALOX5AP gene variants and MI have also been reported. Two studies in the United States reported no correlations between ALOX5AP gene variants and CAD. Also a study with a Japanese population indicated no relationship between the ALOX5AP gene variants and MI. In 2010 a study with a Lebanese population did not find any association between ALOX5AP gene variants and CAD or MI. To add to the debate, in 2015, results of a study with a Lebanese population indicated that different SNP variants in the ALOX5AP gene yielded a different relationship to CAD. Specifically, the genetic variant rs4769874 is significantly associated with an increased risk of CAD, whereas the rs9579646 SNP is significantly associated with a decreased risk of CAD.

b.The LTA4H gene located at 12q23.1 encodes leukotriene A4 hydrolase and is also involved in the inflammation pathway. A haplotype (HapK) in the LTA4H gene moderately increased the risk of MI in a cohort from Iceland. A moderate risk was also found in studies of three US cohorts with European Americans, but HapK, although rarer in African Americans, tripled their risk of MI. It is worthy to note that the HapK is very rare in an African population and evidence of HapK in African-American cohorts may be due to European genetic influence. In 2014, researchers in India reported that LTA4H is significantly associated with CAD. The results of these studies with the ALOX5AP and LTA4H gene variants highlight the need for future studies in different populations. However, they provide the basis for further research to develop new drugs targeting the leukotriene pathway, thereby preventing or reducing the risk of MI and CAD in the future.

B.Connective tissue abnormalities and disease of the aorta. Genetic mutations affecting the connective tissue and extracellular matrix typically affect multiple organ systems, but often the most devastating and lethal effects arise from those upon the cardiovascular system. Aortic dissection and rupture are often the consequences of such abnormalities, and what follows is a brief description of three such disorders.

1.Marfan syndrome. This disorder is inherited in an autosomal dominant fashion with variable penetrance, and it affects the connective tissue, leading to abnormalities of organs of the cardiovascular, skeletal, and ocular systems. In some patients it may be caused by a de novo mutation. The genetic defect is in the fibrillin-1 (FBN1) gene on chromosome 15q21.1. Often, the diagnosis is made on clinical grounds alone. The classic features of tall stature, arachnodactyly, dolichostenomelia, pectus excavatum, ectopia lentis, and a positive family history all support a diagnosis of Marfan syndrome. The cardiovascular system is affected, and the most common cause of death in these patients is from aortic dissection and aortic rupture. Other common related problems include aortic dilation, aortic valve regurgitation, mitral valve prolapse (MVP), tricuspid valve prolapse, and arrhythmias. When patients with Marfan syndrome present with dissection, they are typically younger and do not have hypertension.

The FBN1 gene is responsible for producing a key constituent of microfibrils, which are important in the extracellular matrix. Microfibrils add to the elastic properties of extracellular tissue. Over 1,800 mutations in the FBN1 gene have been recognized and appear to affect different aspects of cellular processing of fibrillin-1. These mutations can vary from a SNP to a premature stop codon. There are no specific relationships between mutations and phenotypes as of yet. Family members with Marfan syndrome and the same FBNI gene mutation may show wide variation in onset and severity of cardiac symptoms. The diagnosis of Marfan syndrome is generally made on a clinical basis. However, genetic testing for Marfan syndrome is available.

2.Ehlers–Danlos syndrome. Ehlers–Danlos syndrome is a group of connective tissue disorders caused by defects in proteins that are involved in the formation of collagen. It is uncommon and usually has an autosomal dominant pattern of inheritance but recessive inheritance pattern is seen also. De novo mutations may cause the condition also. In 1997, Villefranche Nosology classified six distinct subtypes of Ehlers–Danlos syndrome. For the most part these subtypes were based on clinical features and linked to mutations in collagen-related genes. In 2017, the International ED Consortium proposed a new classification with 13 subtypes. Each of these subtypes has its own clinical picture. However, the definitive diagnosis for each of these subtypes, except for the hypermobility type, is based on genetic testing and presence of a causative gene.

The cardiovascular system is involved in two subtypes: the vascular and the cardio-valvular.

a.The vascular subtype has an autosomal pattern of inheritance. The gene, COL3A1, involved in the vascular subtype type of Ehlers–Danlos syndrome, is localized to chromosome 2q32.2 and encodes for type III collagen. Mutations in the gene cause the vascular subtype (vEDS), which accounts for approximately 5% of all Ehlers–Danlos syndrome cases. Vascular complications include dissections of the carotids and the vertebral arteries. There may be arterial rupture of the abdominal vessels such as the renal and hepatic especially at a younger age. Aortic dissections are the primary cause of death and often involve both the thoracic and the abdominal aortas. Up to one-quarter of cases have evidence of aortic aneurysmal involvement. In this vascular subtype hypermobility and skin hyperextensibility are not usually evident. Diagnosis is usually ascertained clinically along with genetic testing for evidence of the mutation in the COL3A1 gene.

b.The cardiac-valvular subtype has a recessive pattern of inheritance. This COL1A2 gene, involved in this subtype, is localized to chromosome 7q21.3 and encodes for a component of type I collagen known as the pro-α2(I) chain. Mutations in the gene result in abnormal collagen. This leads to the severe aortic and mitral valve problems seen in this subtype. Skin hyperextensibility and hypermobility are evident in this subtype also. Diagnosis is usually ascertained clinically along with genetic testing for evidence of the mutation in the COL1A2 gene.

3.Loeys–Dietz syndrome. Loeys–Dietz syndrome is a connective tissue disorder characterized by hypertelorism, cleft palate, and vascular disease in the form of arterial aneurysms and dissection. It is inherited in an autosomal dominant pattern. In many cases it is the result of a de novo mutation. Clinically, these patients are at high risk for aortic dissection. There are six types of Loeys–Dietz syndrome classified according to the gene involved. Mutations in the TGFBR1 gene (chromosome 9q22.33) cause Type I, gene mutations in TGFBR2 (chromosome 3p24.1) result in Type II, mutations in the SMAD3 gene (chromosome 15q22.33) cause Type III, TGFB2 (chromosome 1q41) genetic mutations lead to Type IV, mutations in TGFB3 (chromosome 14q24.3) cause Type V, and mutations in the SMAD2 gene (chromosome 18q21.1) cause Type VI. The mutations in these genes produce proteins with reduced function and interfere with the transforming growth factor–β pathway. Phenotypically, the characteristics are similar to those in Marfan syndrome, and also these patients appear similar (with the exception of the craniofacial abnormalities) to Ehlers–Danlos patients with vascular involvement (type IV). The relevance of this distinction is that those with Loeys–Dietz appear to have much lower intraoperative mortality during corrective vascular surgery. Genetic testing to identify the mutation in one of the known genes, and evidence of either aortic root enlargement or type A dissection, or systemic features is needed for definitive diagnosis.

C.Cardiomyopathies. Primary disease of the myocardium affects both systolic and diastolic function and often results in heart failure or other adverse events over time. Many of the nonischemic cardiomyopathies have a strong genetic component to explain their phenotype. Perhaps, the most clinically relevant entities include dilated cardiomyopathy (DCM) and HCM. Cardiomyopathies can also occur as a secondary process in response to a separate unrelated factor (i.e., hypertension), and it is unknown to what degree genetic susceptibility determines the myocardial response/remodeling over time. Until recently, the classification of cardiomyopathies has been based on the phenotype and morphologic characteristics. However, with an improved knowledge of the genetics of these disorders, a new understanding and appreciation for the underlying mechanisms of disease in these disorders will undoubtedly influence how these entities are diagnosed and treated in the future.

1.Dilated cardiomyopathy. DCM is characterized by dilation of one or both of the ventricular chambers resulting in severe systolic dysfunction and characterized by congestive heart failure. A genetic cause is thought to account for 20% to 50% of DCM cases, and in many cases, the pattern of inheritance is autosomal dominant. However, recessive, X-linked, and mitochondrial patterns of inheritance are also seen. Many cases of DCM are secondary to other etiologies. Mutations in a large number of genes have been associated with this phenotype. To complicate the picture further each gene has many “private” mutations, that is, mutations unique to a particular family. Also, there are often subtle differences in the various types of DCM, such as age of onset and degree of clinical symptoms, all of which may suggest separate genetic abnormalities are at play. Although the products of most of the genes associated with DCM are important structural proteins, there are others involved in the handling of calcium and regulation of energy within the myocytes. Mutations in the sarcomere protein genes account for approximately 10% of familial and 25% of idiopathic DCM. The TTN gene encoding for titin is the most commonly mutated gene in DCM. More than 35 variants of TTN have been associated with DCM, many of these are TTN-truncating variants with variable penetrance. Many mutations associated with sacromere stability, including MLP, VCL, CRYAB, have been linked to DCM. Mutations in LMNA gene, which encodes lamin A and lamin C, are seen in DCM with or without conduction system disease. However, when conduction system disease is present it is severe. Although mutations in SCN5A, a cardiac sodium channel gene, are also associated with this type of DCM, the clinical picture differs as ventricular dysfunction is usually present. Mutations in the Dystrophin and EMD genes have been identified in X-linked recessive DCM. Mutations in the ALMS1 and GATAD1 genes are transmitted in an autosomal recessive pattern. Genetic testing is available for many of the gene mutations that have been identified. Table 39.1 lists some of the genetic variants that are believed to be associated with various DCM phenotypes.

TABLE 39.1 Selected Genetic Variants Associated with Dilated Cardiomyopathy
Gene	Chromosome Location	Mode of Inheritance	Gene Product and Function
ACTC1	15q11-q14	Autosomal dominant	Sarcomeric gene—encodes cardiac actin Vital part of contractile apparatus of myocyte
CSRP3	11p15	Autosomal dominant	Encodes cardiac muscle LIM protein Functions as a stretch sensor in myocyte
DES	2q35	Autosomal dominant	Encodes desmin—cytoskeletal protein involved in stabilization of sarcomere and mutation may affect contractile force
Lamin A/C (LMNA)	1q22	Autosomal dominant	Encodes lamin A and lamin C Structural proteins—affect structure of nucleus in myocytes
MYBPC3	11p11.2	Autosomal dominant	Encodes cardiac myosin-binding protein C Mutations may affect contractile mechanism
MYH6	14q12	Autosomal dominant	Sarcomere gene—encodes α-myosin heavy chain Mutations may affect contractile mechanism
MYH7	14q11	Autosomal dominant	Sarcomere gene—encodes β-myosin heavy chain Mutations may affect contractile mechanism
PLN	6q22	Autosomal dominant	Phospholamban—controls muscle relaxation through calcium regulation via calcium ATPase
PSEN1/2	14q24.3 (PSEN1) 1q31-q42 (PSEN2)	Autosomal dominant	Presenilin —PSEN1 encodes presenilin 1 PSEN2 encodes presenilin 2 Transmembrane proteins
SCN5A	3p21	Autosomal dominant	Cardiac sodium channel gene
TMPO	12q22	Autosomal dominant	Encodes thymopoietin—maintains functional integrity of nucleus
TNNI3	19q13.42	Autosomal dominant	Encodes cardiac troponin I Mutations may affect contractile mechanism
TNNC1	3p21.1	Autosomal dominant	Encodes troponin C1(TnC) Mutations may affect contractile mechanism
TNNT2	1q32	Autosomal dominant	Sarcomere gene—encodes troponin T type Mutations may affect contractile mechanism
TPM1	15q22	Autosomal dominant	Encodes α-tropomyosin Mutations may affect contractile mechanism
Dystrophin (DMD)	Xp21.2	X-linked recessive	Encodes dystrophin Mutations can affect transduction of contractile force
EMD	Xq28	X-linked recessive	Encodes for Emerin, a component of the nuclear envelope Autosomal recessive DCM
ALMS1	2p13.1	Autosomal recessive	Alstrom syndrome Encodes for protein associated with hearing impairment, vision, obesity, and type 2 diabetes
GATAD1	7q21.2	Autosomal recessive	Encodes a protein containing a zinc finger at the N-terminus, and it is thought to have a role in regulating gene expression

DCM, dilated cardiomyopathy.

2.Hypertrophic cardiomyopathy. HCM (see Chapter 10) is a highly variable and heterogeneous disease process that affects the myocardium, with clinical manifestations varying from completely asymptomatic to severe (sudden cardiac death). The broad range of phenotypes and significant selection bias resulted in an overestimation of the mortality rate associated with this disease. The clinical spectrum of the disease is wide, and the ability to accurately predict outcomes remains challenging. The clinical variability of HCM is not only limited to the presenting phenotype but also related to age of presentation, clinical course, and eventual outcomes, making it very challenging to properly identify a phenotype of interest. The characteristic phenotype is an asymmetrically hypertrophied myocardium with a small ventricular chamber and occasionally a left ventricular (LV) outflow tract pressure gradient (with systolic anterior motion of the mitral valve) and/or an intracavitary gradient.

More than 1,400 known mutations in at least 50 separate genes have been identified, with the majority of mutations in two genes: MYH7 on chromosome 14 and MYBPC3 on chromosome 11. These genes encode proteins of the cardiac sarcomere unit, specifically the product of MYH7 is β-myosin heavy chain, whereas MYBPC3 encodes myosin-binding protein C. Mutations in additional sarcomere genes are involved in HCM also. These genes include TNNT2 (troponin T), TNNI3 (troponin I), MYL2 (myosin light chains), MYL3 (myosin light chain 3), TPM1 (α-tropomyosin), and ACTC (actin). Mutations in non-sarcomeric genes and Z-disc encoding genes have also been identified in HCM. The importance of properly characterizing a phenotype as heterogeneous as HCM has been illustrated by the example of glycogen storage diseases mimicking the appearance of HCM. Mutations in the genes for adenosine monophosphate-activated protein kinase γ2 (PRKAG2) and lysosome-associated membrane protein 2 (LAMP2) were found in phenotypes that closely resembled HCM but were differentiated based on serum protein levels and ventricular preexcitation.

3.Arrhythmogenic right ventricular cardiomyopathy. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a primary abnormality resulting in fibrofatty infiltration of the myocardium, primarily the right ventricle. Clinical manifestations include right ventricular dysfunction and lethal ventricular arrhythmias. Diagnosis often requires a battery of tests, including an electrocardiogram demonstrating repolarization abnormalities and an epsilon wave, magnetic resonance imaging or computed tomography demonstrating fibrofatty infiltration of the right ventricle, and endomyocardial biopsy. Often a positive family history of the disorder is present. ARVC is usually inherited in an autosomal dominant with incomplete penetrance (in most cases). Thirteen chromosomal locations have been identified for ARVC and mutations associated with ARVC have been identified in specific genes at 11 of these locations. Eleven of these genes encode five desmosomal proteins (desmoplakin, desmoglein, plakophilin-2, desmocollin 2, and plakoglobin), and six non-desmosomal proteins (desmin, Titin, transmembrane protein 43, transforming growth factor β-3, ryanodine receptor 2, and α-catenin). The specific genes for ARVC3 and ARVC6 have not yet been identified although the chromosomal loci are known. Other genes have been reported as being implicated in ARVC: PLN encodes for phospholamban, LMNA encodes lamin A/B, and SCN5A gene encodes for sodium channels. In ARVC 8 mutations in the DSP gene, encoding desmoplakin, have an autosomal dominant pattern of inheritance, whereas mutations in the same DSP gene with an autosomal recessive inheritance result in Carvajal syndrome. Similarly, in ARVC12, mutations in the JUP gene encoding plakoglobin have an autosomal dominant pattern of inheritance, whereas mutations in the same JUP gene with an autosomal recessive inheritance result in Naxos disease, a variant associated with the triad of ARVC along with dermatological manifestations such as wooly hair and palmoplantar keratoderma. Variants of ARVC are distinguished on the basis of the gene involved and are described further in Table 39.2.

TABLE 39.2 Genetic Variants of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
ARVC Variant	Chromosome Locus/Gene	Gene Product and Function
ARVC1	14q24.3/TGF B3	Encodes for transforming growth factor–β-3 involved in embryogenesis and cell differentiation
ARVC2	1q43/RYR2	Encodes ryanodine receptor 2 involved in Ca²⁺ release into cytosol
ARVC3	14q12-q22/Unknown	In 1996, discovered in a study of three small families
ARVC4	2q32.1-q32.3/TTN	Encodes for Titin, an essential component of sacromeres and has a role in cardiac muscle
ARVC5	3p25.1/TMEM43	TMEM43 may have an important role in maintaining nuclear-envelope structure. It is needed for keeping Emerin in inner nuclear membrane
ARVC6	10p14-p12/Unknown
ARVC7	2q35/DES	Encodes the protein Desmin. Important role in maintaining structure of sacromeres. Found in cardiac muscles
ARVC8	6p24.3/DSP	Encodes Desmoplakin, a constituent protein of desmosomes
ARVC9	12p11.21/PKP2	Encodes for plakophilin 2 and is one of several proteins that make up desmosomes. Found primarily in the myocardium,
ARVC10	18q12.1/DSG2	Encodes for desmogleins involved in desmosome cell adhesion
ARVC11	18q12.1/DSC2	Encodes for desmocollin 2, a major component of desmosomes
ARVC12	17q21.2/JUP	Encodes plakoglobin found primarily in cells of the heart and skin, constituent of adherens junctions and desmosomes
ARVC13	10q21.3/CTNNA3	Encodes a protein from the vinculin/α-catenin family. Has a role in cell–cell adhesion.

From Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), {date}. World Wide Web URL: https://omim.org/

4.Left ventricular noncompaction. LV noncompaction (LVNC) is a relatively rare congenital abnormality of the myocardium resulting in a trabeculated appearance of the LV cavity. It is characterized by spongy myocardium that results from arrest in endomyocardial morphogenesis. It is seen in <1% of adults. This disorder can occur in isolation or in association with other congenital anomalies or with chromosomal abnormalities. These chromosomal abnormalities are rare and include chromosomal deletion, trisomy, Robertsonian translocation, and mosaicism. When LVNC is present with a congenital abnormality, the cause is related to the gene associated with that abnormality. Over time, it is thought that noncompaction can proceed to DCM with severe systolic dysfunction. LVNC is inherited mainly through an autosomal dominant mode of transmission but X-linked transmission is also seen. Mutations in two sarcomere genes, MYH7 and MYBPC3, are responsible for almost a third of LVNC cases. The genes that have been reported mainly encode for sarcomeric, Z-disc and nuclear-envelope proteins as well as mitochondrial proteins. A mutation in the α-dystrobrevin gene (DTNA) on chromosome 18q12.1 has been linked to LVNC1. Mutations for LVNC2 and LVNC3 have been identified on chromosome 11p15 (LVNC2 and chromosome 10q23 (LYNC3) respectively. LVNC variants have been mapped specifically to mutations of the sarcomere genes: LVNC4 is linked to mutation in the ACTC1 gene (chromosome 15q14), LVNC5 to a mutation in the MYH7 gene (chromosome 14q12), and LVNC6 caused by mutation in the TNNT2 gene (chromosome 1q32). Mutation in the MIB1 gene (chromosome 18q11) is linked to LVNC7, whereas LVNC8 is caused by mutation in the PRDM16 gene (chromosome 1p36), LVNC9 is brought about by mutation in the TPM1 gene (chromosome 15q22). Mutation in the MYBPC32 gene (chromosome 11p11) is implicated in LYNC10. There is also an X-linked form of LVNC, Barth syndrome, caused by mutation in the TAZ gene on chromosome Xq28 that encodes tafazzin (TAZ), a mitochondrial protein.

D.Arrhythmogenic disorders

1.Brugada syndrome. Disorders of the conduction system of the heart lead to significant clinical manifestations, most notably ventricular arrhythmias and sudden cardiac death. Two entities, long QT syndrome (LQTS) and Brugada syndrome, have been well described, and their respective genetic abnormalities have been characterized. Brugada syndrome was initially described by Josep and Pedro Brugada in 1992. Clinically, ventricular arrhythmias and sudden cardiac death occur, particularly in middle-aged men. Characteristic electrocardiographic features can help make the diagnosis, and, in some cases, certain drugs, including sodium channel blockers and tricyclic antidepressants, can unmask the abnormality on a surface electrocardiogram. Brugada syndrome is typically inherited in an autosomal dominant pattern with incomplete penetrance. It appears that the penetrance is age and sex dependent. However, a de novo mutation can occur in approximately 1% of cases. Mutations in more than 15 genes have been identified as causing Brugada syndrome: SCN5A, SCN1B, SCN2B, SCN3B, SCN10A, RNGRF, GPD1-L, HCN4, KCNE3, GPD1L, HCN4, KCNE3, KCND3, KCNJ8, KCNE5, CACNA1C, CACNB2, CACNA2D1, TRPM4, SLMAP, and the PKP2 gene. The SCN5A gene with approximately 300 known mutations is the gene most commonly associated with Brugada syndrome and accounts for approximately of 25% of cases. It has been mapped to chromosome 3p22.2 and is a voltage-gated sodium channel gene. SCN1B (chromosome 19q13.12), SCN2B (chromosome 11q23.3) SCN3B (chromosome 11q24.1), and SCN10A (chromosome 3p22.2) are also voltage-gated sodium channel genes. The RANGRF gene on chromosome 17p13 encodes a protein involved in the function of the Nav1.5 cardiac sodium channel. GPD1-L, an NAD-dependent glycerol-3-phosphate dehydrogenase gene, is associated with chromosome 3p22.3. HCN4, on chromosome 15q24, is a hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 gene. KCNE3 (chromosome 11q13.4), KCND3 (chromosome 1p13.2), KCNJ8 (chromosome 12p12.1) are voltage-gated potassium channel genes also. KCNE5 (chromosome Xq22.3) is an X-linked potassium voltage-gated channel gene. CACNA1C (chromosome 12p13.33) and CACNB2 (chromosome 10p12.33-10p12.31) are two subunits of the L-type voltage-dependent calcium channels, whereas CACNA2D1 gene (chromosome 7q21.11) and TRPM4 gene (chromosome 19q13.33) are other calcium voltage–gated genes. The SLMAP gene (chromosome 3p14.3) is implicated in encoding an element of a conserved striatin-interacting phosphatase and kinase complex. PKP2 gene (chromosome 12p11.21) encodes plakophilin 2. In addition, some modifier genes have also been identified. Genetic testing in Brugada syndrome is used to confirm a clinical diagnosis. A negative result does not necessarily exclude the diagnosis. It may reflect that the individual does not have the condition, but it may also mean that the individual either has a mutation in a gene not part of the testing panel or has a mutation in a Brugada-associated gene not included in the panel or the mutation is yet undiscovered. Approximately only one-third of clinically diagnosed cases are found to have a genetic cause despite the large number of genes associated with Brugada syndrome.

2.Long QT syndrome. LQTS encompasses a range of disorders characterized clinically by syncope and sudden cardiac death, with electrocardiographic abnormalities in the QT interval and in the T-wave morphology. LQTS is usually inherited in an autosomal dominant pattern. Recessive inheritance, seen in Jervell and Lange-Nielsen types 1 and 2, is rare. De novo mutations are uncommon. There are approximately 15 different types of LQTS based on the type of gene involved. Of these known genes KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) are the most frequently identified and account for approximately 75% of cases. Each of the remaining 12 genes account for less than 1% of cases. Approximately 20% of clinically diagnosed LQT is not linked to a variant in a known gene. The various forms of LQTS are often distinguishable by clinical features and genetic abnormalities. One such distinguishing feature is that those with LQT1 are typically at higher risk during periods of exercise, whereas those with the LQT3 variant are at higher risk during sleep. The KCNQ1 gene encodes the catecholamine-sensitive portion of the potassium channel responsible for conducting the delayed rectifier current (I_Ks) in the LQT1 variant, whereas the SCN5A gene is affected in the LQT3 variant. The underlying defect involving the sodium channel results in a prolonged depolarization current, whereas defects involving the potassium channel result in a longer QT duration secondary to inability to reestablish repolarization within the myocyte. The autosomal recessive phenotypes (Jervell and Lange-Nielsen types 1 and 2) are associated with bilateral sensorineural hearing loss.

Hundreds of mutations are involved in LQTS. However, most of the prognostic information available is based on the gene involved and not the specific mutation. Having the genotypic information can help in prognosis and in determining response to therapy. The rates of ventricular arrhythmias and sudden cardiac death vary based on the gene involved, as does the response to therapy. This information may be particularly helpful in trying to decide between medical therapy, implantable cardioverter–defibrillator implantation, or both. Table 39.3 lists the variants of LQTS and the genes involved.

TABLE 39.3 Genetic Variants Associated with Long QT Syndrome
LQT Variant	Gene	Chromosome Locus	Mode of Inheritance	Protein
LQT1	KCNQ1	11p15.5	Autosomal dominant	Catecholamine-sensitive portion of I_K potassium channel
LQT2	KCNH2	7q35-36	Autosomal dominant	α-Subunit of I_Kr potassium channel
LQT3	SCN5A	3p21-24	Autosomal dominant	Cardiac sodium channel
LQT4	ANK2	4q25-27	Autosomal dominant	Ankyrin protein
LQT5	KCNE1	21q22.12	Autosomal dominant	β-Subunit of I_Ks potassium channel
LQT6	KCNE2	21q22.11	Autosomal dominant	β-Subunit of I_Ks potassium channel
LQT7	KCNJ2	17q23	Autosomal dominant	Subunit of I_Kr potassium channel
LQT8	CACNA1C	12p13.3	Autosomal dominant	Subunit of the L-type voltage-dependent calcium channel
LQT9	CAV3	3p25	Autosomal dominant	Encodes caveolin-3, found in the membrane surrounding muscle cells CAV3 gene mutations may affect the function of sodium channels
LQT10	SCN4B	11q22.3	Autosomal dominant	β-voltage–gated sodium channel subunit
LQT11	AKAP9	7q21-22	Autosomal dominant	Encodes the A-kinase anchor protein-9
LQT12	SNTA1	20q11.2	Autosomal dominant	Syntrophin α-1 peripheral membrane protein associated with dystrophin, and dystrophin-related proteins
LQT13	KCNJ5	11q24.3	Autosomal dominant	G protein–activated inward rectifier potassium channel 4
LQT14	CALM1	14q32.11	Autosomal dominant	Calmodulin 1, a calcium binding protein
LQT15	CALM2	2p21	Autosomal dominant	Calmodulin 2, a calcium binding protein
Jervell and Lange-Nielsen type 1	KCNQ1	11p15.5-15.4	Autosomal recessive	Subunit I_K channel
Jervell and Lange-Nielsen type 2	KCNE1	21q22.12	Autosomal recessive	β-Subunit of I_Ks potassium channel

3.Atrial fibrillation. AF is the most common of the arrhythmic disorders. The majority of adult-onset familial AF is inherited in an autosomal dominant pattern. In 2003, the first genetic mutation for AF was identified as an S140G mutation in KCNQ1. This mutation is responsible for a gain of function in the IKs channel complex. Mutations implicated in gain-of-function effects as well as loss-of-function effects on IKs have been reported. The majority of the mutations linked to AF have been found in the potassium ion channel genes (KCNQ1, KCNE1, KCNE2, KCNE3 and KCNE5, KCNJ2, and KCNH2). The connexin 40 gene (GJA5) has also been implicated. Mutations in SCN5A encoding four regulatory β-subunits can cause AF also. Germline and somatic mutations have also been associated with AF.

The first GWAS study, in 2006, identified that the SNPs associated with AF were on chromosome 4q25. In that study SNP, rs2200733, was the most significant identified in European, Asian, and African populations. The 4q25 variants are near the PITX2 gene, which is involved in left–right symmetry of the heart in development. It has not yet been proven how the variants at 4q25 exert their effect. SNPS associated with AF have been identified on at least 10 different chromosomes. Owing to the relatively small number of mutations identified for familial AF coupled with the genetic complexity, it is quite possible that there are many more mutations for familial AF that are still unknown.

E.Valvular heart disease

1.Mitral valve prolapse. Nonsyndromic MVP (see Chapter 16) is a common disorder that appears to have a strong genetic component, and the familial form is inherited in an autosomal dominant pattern with variable penetrance dependent on sex and age. Presentation of MVP may vary even within members of the same family. In addition, it occurs in an idiopathic form, and it is also associated with other valvular syndromes such as bicuspid aortic valve (BAV) and connective tissue diseases, which typically affect cardiovascular function such as Marfan syndrome (syndromic MVP), osteogenesis imperfecta, and Ehlers–Danlos syndrome. Prolapse of the mitral valve occurs primarily because of abnormalities in the connective tissue matrix of the valve itself. Myxomatous degeneration of the valve tissue leads to redundant tissue and weakening of both the valve and the subvalvular apparatus. Clinically, this manifests as displacement of the mitral valve leaflets into the left atrium during systole and may progress to mitral regurgitation and eventual congestive heart failure with occasional rupture of the chordae. Although surgical repair and replacement have improved the long-term prognosis of this disorder, understanding the genetic basis of this disease may allow the earlier diagnosis and development of therapies to prevent progression.

Three chromosomal locations have been identified with MVP inherited in an autosomal dominant manner. These are MMVP1 (chromosome 16p12.1-11.2), MMVP2 (chromosome 11p15.4), and MMVP3 (chromosome 13q31.1-32.1). X-linked myxomatous valvular dystrophy (XMVD) has been mapped to chromosome Xq28, and the P637Q mutation in the filamin A gene (FLNA) has been identified as a cause of XMVD. Additional mutations in the FLNA gene have been linked to X-linked MVP/XMVD. In 2015, the DCHS1 gene at the chromosomal location for MMVP2 was discovered. This gene is a member of the cadherin superfamily and encodes calcium-dependent cell–cell adhesion molecules. A loss-of –function mutation (R2513H) in this gene is implicated in MVP. Additional mutations in this gene have been identified and their links to MVP are being investigated. In 2015, three loci, 2q35, 17p13, and 22q12, associated with MVP were identified.

2.Aortic valve disease. Aortic valve disease (see Chapter 15) can be divided into two different types based on clinical characteristics: BAV and calcific trileaflet aortic valvular disease. Calcific aortic valvular disease is typically a disease of the elderly. It was thought to be affected by those risk factors predisposing toward CAD but more recently is recognized as a separate condition from atherosclerosis. BAV is believed to be a congenital abnormality with an autosomal dominant mode of transmission with reduced penetrance. The prevalence of BAV in first-degree relatives of affected individuals has been reported as being as high as 9%. BAV is present in 0.2% to 2% of the population and is typically discovered earlier on in life and is frequently associated with disease of the aorta. What BAV and calcific aortic valvular disease have in common is the eventual progression to calcification of the aortic valve itself. Mutations in the NOTCH1 gene located on chromosome 9 at q34.3 have been implicated in BAV development. NOTCH1 is a transmembrane protein with transcriptional regulatory activity that is vital not only for aortic valve development but also for calcification. It is thought that mutations in this gene may allow the normally repressed transcription factor Runx2 to facilitate the development of valvular endothelial cells into osteoblast-like cells and promote valvular calcification. Mutations in the ACTA2 gene on chromosome 10q23.3, which codes for actin, have also been linked to BAV. Mutations in ubiquitin fusion degradation 1-like gene, located at 22q11.21, have also been implicated in BAV. This gene codes for a signaling protein that is prevalent during embryonic formation of cardiac outflow tracts. Another gene implicated in BAV is the GATA5 gene on chromosome 20q13.33 encoding for a protein that is a transcription factor containing two GATA-type zinc fingers. This protein is necessary for cardiovascular development. Recent studies have identified associations between loss-of-function mutations of the GATA5 gene and BAV. In 2014, Qu et al. reported that a loss-of-function mutation in the NXK2-5 gene, location 5q35.1, was associated with BAV in a Chinese family. The NXK2-5 gene encodes a homeobox-containing transcription factor that is involved in cardiac embryological development. Mutations in this gene are known to cause atrial septal defect, and tetralogy of Fallot. Three additional loci associated with BAV have been identified on the long arms of chromosomes 5, 13, and 18, but no specific genes have been discovered. Interestingly, in 2014, Researchers using a targeted next-generation sequencing approach identified variants in 26 genes not previously implicated with BAV in humans. It is evident that many different genes are implicated in BAV and calcific aortic valvular disease

F.Inborn errors of metabolism. Cardiovascular disease is often a manifestation of genetic abnormalities in separate pathways, which produce secondary effects upon the cardiovascular system. Many of these genetic mishaps occur in multiple pathways essential to metabolism, and their resultant phenotypes often impose upon the cardiovascular system. Table 39.4 lists some examples of metabolic abnormalities and the associated cardiac manifestations.

TABLE 39.4 Cardiovascular Manifestations of Systemic Metabolic Disease
Metabolic Disorder	Gene/Protein Defect	Effect upon Cardiovascular System	Comments
Fabry disease	GLA gene mutations cause α-galactosidase deficiency causes an accumulation of globotriaosylceramide	LV hypertrophy, RV, hypertrophy, valvular heart disease, mitral valve prolapse, hypertrophy of papillary muscles, aortic dilatation, atrial enlargement, diastolic function may be impaired, lethal arrhythmias, and coronary ischemia	X-linked lysosomal storage disorder
Hereditary hemochromatosis (classified by Type)	HFE gene mutations cause defect in MHC class I-like protein (Type 1) HJV gene mutations cause defect in hemojuvelin (Type 2) HAMP gene mutations cause defect in hepcidin (Type 2) TFR2 gene mutations cause defect in transferrin receptor-2 (Type 3) SLC40A1 gene mutations cause defect in ferroportin (Type 4)	Abnormal proteins involved in iron absorption and storage lead to excess iron deposition in the heart and results in cardiomyopathy, cardiomegaly, heart failure, and arrhythmia	Types 1, 2, and 3 Autosomal recessive Type 1, most common—adult onset Type 2—juvenile-onset Type 3—Onset between juvenile and adult Type 4 autosomal dominant, adult onset
Niemann–Pick disease (classified by Types A, B, and C)	SMPD1 gene mutations cause defect in sphingomyelinase (Types A and B) NPC1 or NCP2 gene mutations cause defect in proteins implicated in lipid transport (Type C)	Accumulation of sphingomyelin in cardiac tissue leading to cardiomegaly (Types A and B) Serum triglycerides and LDL-cholesterol often elevated, HDL-cholesterol is low (Type B) Abnormal accumulation of lipids in the lysosomes, and cell dysfunction because of lack of lipids within various tissues leads to tissue and organ damage (Type C)	Autosomal recessive Type A do not survive past first few years of life Type B (not as severe as Type A) Mid-childhood onset, usually survive into adulthood Type C Childhood onset—may survive into adulthood
Mucopolysaccharidosis type I (MPS I) Classified into severe (Hurler syndrome) and attenuated (Hurler–Scheie syndrome; Scheie syndrome) types	Mutations in IDUA gene cause deficiency in α-l-iduronidase	Biventricular enlargement, endocardial fibrosis, and valvular disease Severe MPS I results in cardiorespiratory failure with first 10 years of life	Autosomal recessive Severe MPS I appear normal at birth, symptoms within first year. Attenuated MPS I onset 3–10 years age
Mucopolysaccharidosis type II (MPS II) Hunter syndrome Classified into severe and mild types	Mutations in the IDS gene cause deficiency in iduronate-2-sulfatase	Accumulation of glycosaminoglycans within lysosomes leading to cardiac involvement including valvular disease that can lead to ventricular hypertrophy and heart failure. Cardiac disease major cause of morbidity	X-linked recessive lysosomal storage disorder Severe MPS II—life expectancy 10–20 years Mild MPS II survive into adulthood
Danon disease	Mutations in the LAMP2 gene cause deficiency in lysosome-associated protein-2	Cardiac involvement includes palpitations, arrhythmia, left VH, CHF, hypertrophic or dilated cardiomyopathy, and preexcitation (Wolff–Parkinson–White syndrome usually)	X-linked dominant Males more severely affected (life expectancy 19 years) than females (life expectancy 34 years)
Gaucher disease (cardiovascular type) Autosomal recessive	Mutations in GBA gene cause deficiency of β-glucocerebrosidase	Accumulation of glucocerebroside leading to cardiomyopathy, also calcification of aorta and aortic and mitral valves
Pompe disease Classified by type: classic infantile-onset, nonclassic infantile-onset, and late-onset.	Mutations in GBA gene cause deficiency in acid α-glucosidase	Accumulation of glycogen causes biventricular concentric hypertrophic cardiomyopathy, arrhythmias, heart failure	Autosomal recessive
Primary carnitine deficiency	Mutations in SLC22A5 gene result in absent or dysfunctional OCTN2 protein resulting in carnitine deficiency.	Accumulation of fatty acids associated with cardiomegaly, hypertrophic or dilated cardiomyopathy, heart failure, and sudden death	Autosomal recessive, severity varies, carnitine transport is vital for mitochondrial function

CHF, congestive heart failure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LV, left ventricular; MHC, major histocompatibility complex; RV, right ventricular; VH, ventricular hypertrophy.

G.Chromosomal abnormalities and cardiovascular disease. Chromosomal abnormalities that occur at the time of development can have serious implications with regard to the proper growth and development of a child. Although neuropsychiatric development is often delayed, the cardiovascular system is also affected in many of these disorders and often survival may be limited owing to the severity of congenital cardiac defects. Table 39.5 lists common syndromes associated with chromosomal structural abnormalities and the associated cardiovascular findings.

TABLE 39.5 Common Chromosomal Abnormalities and Associated Cardiovascular Disease
Syndrome	Chromosomal Abnormality	Associated Cardiovascular Abnormality
Down syndrome	Trisomy 21	Endocardial cushion defect, VSD, PDA, and tetralogy of Fallot
Turner syndrome	45X	Coarctation of the aorta, bicuspid AV, and anomalous PV return, aortic dissection
Patau syndrome	Trisomy 13	Dextrocardia, VSD, ASD, endocardial cushion defect, hypoplastic left heart, tetralogy of Fallot, coarctation of the aorta, and PDA
Edward syndrome	Trisomy 18	VSD, ASD, endocardial cushion defect, coarctation of the aorta, hypoplastic left heart, tetralogy of Fallot, pulmonary valve stenosis, PDA and persistent left SVC
Fragile X syndrome	FMR1 gene (X chromosome) with trinucleotide repeats	Mitral valve prolapse, aortic root dilation

ASD, atrial septal defect; AV, aortic valve; PDA, patent ductus arteriosus; PV, pulmonary vein; SVC, superior vena cava; VSD, ventricular septal defect.

ACKNOWLEDGMENTS: The authors acknowledge the contribution of Dr. Eric Topol and Dr. Saif Anwarrudin to an earlier version of this chapter.