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(Circulation. 1995;92:142-147.)
© 1995 American Heart Association, Inc.

Articles

Genetic Approaches to Cardiovascular Disease

Supravalvular Aortic Stenosis, Williams Syndrome, and Long-QT syndrome

Mark T. Keating, MD

From the Howard Hughes Medical Institute, Eccles Institute of Human Genetics, and Cardiology Division, University of Utah Health Sciences Center, Salt Lake City.

Correspondence to Dr Mark Keating, Eccles Institute of Human Genetics, University of Utah, Building 533, Room 2100, Salt Lake City, UT 84112.

	Abstract

Top Abstract Introduction SVAS, an Inherited Vascular... Haploinsufficiency of Elastin... Molecular Genetic Studies of... HERG and SCN5A... Clinical Implications Summary References

 
Background Although family history can be an important risk factor for cardiovascular disease, relatively little is known about the nature of specific genetic risk factors. One approach to this problem is to identify and characterize genes responsible for inherited disorders in the hope that this information will also provide mechanistic insight into common forms of cardiovascular disease.

Methods and Results Over the last decade, it has become possible to identify genes that cause human disease by use of the techniques of molecular genetics, specifically genetic linkage analysis, positional cloning, and mutational analyses. We have used these techniques to study three inherited cardiovascular disorders: supravalvular aortic stenosis, Williams syndrome, and long-QT syndrome. We have discovered that the vascular pathology of supravalvular aortic stenosis and Williams syndrome results from mutations involving the elastin gene on chromosome 7q11.23. These mutations include intragenic deletions, translocations, and complete deletion of the elastin gene, suggesting that a quantitative reduction in elastin during vascular development is pathogenically important. To date, only the elastin gene has proved important for supravalvular aortic stenosis. By contrast, genetic linkage analyses in families with long-QT syndrome indicate that at least four distinct genes can cause this disorder. We have identified three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Recently, we demonstrated that mutations in a putative cardiac potassium channel gene, HERG, are responsible for the chromosome 7–linked form of long-QT syndrome, whereas mutations in the cardiac sodium channel gene SCN5A cause the chromosome 3–linked form of this disorder. HERG mutations and potassium channel biophysics suggest a dominant-negative molecular mechanism and reduced repolarization currents. By contrast, SCN5A mutations probably cause subtle alterations of cardiac sodium channel function and prolonged depolarizing currents.

Conclusions Molecular genetic analyses of long-QT syndrome, supravalvular aortic stenosis, and Williams syndrome have begun to unravel the mechanisms underlying these inherited disorders. Rapid genetic testing for Williams syndrome is now available using a simple cytogenetic test, fluorescence in situ hybridization, but additional work will be required for long-QT syndrome and autosomal-dominant supravalvular aortic stenosis. Improved diagnosis and mechanistic understanding of these disorders should lead to rational treatment and prevention.

Key Words: arrhythmias • stenosis • genes

	Introduction

Top Abstract Introduction SVAS, an Inherited Vascular... Haploinsufficiency of Elastin... Molecular Genetic Studies of... HERG and SCN5A... Clinical Implications Summary References

 
One's genetic heritage plays an important role in the risk of developing cardiac disease. Unfortunately, the identity and relative importance of genetic risk factors remain largely obscure. To identify genes involved in cardiovascular disease, investigators have focused on the identification and characterization of physiological abnormalities associated with a particular disorder. If a protein could be associated with this abnormality, further characterization of the gene encoding the protein might yield results. Over the last decade, however, it has become possible to reverse this process by studying the genetics of an inherited disorder and working back to the protein and physiology. This process, often called molecular genetics, requires no physiological or biochemical information. I recently reviewed the premise and details of molecular genetics for Circulation.¹ The purpose of this article is to review our progress in three inherited cardiovascular disorders: supravalvular aortic stenosis (SVAS), Williams syndrome (WS), and long-QT syndrome (LQT).

	SVAS, an Inherited Vascular Disease, Results From Mutations in the Elastin Gene

Top Abstract Introduction SVAS, an Inherited Vascular... Haploinsufficiency of Elastin... Molecular Genetic Studies of... HERG and SCN5A... Clinical Implications Summary References

 
SVAS is an autosomal-dominant inherited disorder that causes obstructive arterial disease.^{2 3} The most pronounced effects of SVAS are on large vessels, such as the aorta and pulmonary arteries, but this disorder involves all arteries, including the carotid and coronary arteries (Fig 1). SVAS often presents in childhood, and if not corrected by surgery, can lead to heart failure and death.

View larger version (158K): [in this window] [in a new window]   Figure 1. Aortogram showing supravalvular aortic stenosis.

Relatively little was known about the pathogenesis of SVAS. Pathological studies demonstrated disease in the intima and media of affected arteries, including disruption of elastic fibers, hypertrophy of smooth muscle cells, disruption of the intima, and intimal proliferation of smooth muscle and fibrosis. Since physiological and biochemical approaches to this disorder had not been successful, we used a genetic approach.

In 1992, we discovered genetic linkage between the SVAS phenotype and DNA markers on the long arm of chromosome 7 (Fig 2).³ A polymorphism at the elastin locus was completely linked to the phenotype, making elastin an exciting candidate gene. We tested this hypothesis and identified inherited and de novo rearrangements (1 translocation, 2 partial deletions, and 131 complete deletions) of the elastin gene in DNA samples from patients with SVAS (Fig 3).^{6 7 8 9} Olson and colleagues⁵ independently identified linkage between SVAS and chromosome 7 and recently identified an intragenic deletion of the elastin gene associated with the disorder. No elastin rearrangements were identified from samples from control individuals. These data, coupled with existing knowledge of vascular histology and physiology, indicate that mutations of the elastin gene cause this vascular disorder (Table 1).

View larger version (20K): [in this window] [in a new window]   Figure 2. Idiogram of chromosomes 3, 7, and 11 showing the chromosomal location of the elastin gene (supravalvular aortic stenosis), HERG (LQT2), SCN5A (LQT3), and LQT1.

View larger version (38K): [in this window] [in a new window]   Figure 3. Diagrams show that mutations in the elastin gene cause an inherited vascular disease, supravalvular aortic stenosis. The elastin gene consists of alternating hydrophobic and cross-linking domains. The elastin monomer is thought to interact with the microfibrillar scaffold to form elastic fibers.

View this table: [in this window] [in a new window]   Table 1. Molecular Genetics of SVAS and WS

The pathogenic mechanisms underlying SVAS are not yet understood. Reduced elastin content in the media of developing vessels may lead to recurrent injury and fibrosis (Fig 4). Vascular inelasticity, in turn, may increase hemodynamic stress to the endothelium, leading to intimal proliferation of smooth muscle and fibroblasts, fibrosis, and luminal narrowing. Alternatively, quantitative or qualitative abnormalities in the internal elastic lamina may impair its function as a boundary for information and cell proliferation. Finally, elastic fiber abnormalities may increase elastin degradation, and elastin degradation products are known chemotactic factors for inflammatory cells. Because these mechanistic hypotheses cannot be tested using human pathological specimens, we are developing a mouse model for SVAS using homologous recombination. Once an animal model is available, we should be able to determine whether medical therapy (eg, reduced hemodynamic stress from ß-blockers) is feasible.

View larger version (59K): [in this window] [in a new window]   Figure 4. Drawing showing normal vascular structures that may be affected by elastin mutations in supravalvular aortic stenosis.

	Haploinsufficiency of Elastin and Adjacent Sequences in WS

Top Abstract Introduction SVAS, an Inherited Vascular... Haploinsufficiency of Elastin... Molecular Genetic Studies of... HERG and SCN5A... Clinical Implications Summary References

 
WS is a complex developmental disorder characterized by congenital heart and vascular disease, mental retardation, a characteristic learning profile, a hypersocial personality, and infantile hypercalcemia.¹⁰ Because the vascular disease in WS is similar to SVAS, we hypothesized that mutations involving the elastin gene might also be responsible for this disorder.

In 1993, we discovered that WS results from submicroscopic deletion of chromosome 7q11.23 (Fig 5).^{7 9 10} Inherited or de novo deletion of one elastin allele was identified in each of the patients studied. We used these data to develop a simple and accurate diagnostic test for WS, fluorescence in situ hybridization with probes at the elastin locus. This test is now available in many medical centers.

View larger version (0K): [in this window] [in a new window]   Figure 5. Hemizygosity of the elastin locus in Williams syndrome. Fluorescence in situ hybridization of metaphase chromosomes from a patient with Williams syndrome shows the lack of an elastin signal in one chromosome.

Our data suggest that hemizygosity at the elastin locus is responsible for vascular pathology in WS. Elastin hemizygosity may also account for other connective tissue abnormalities, including hypertension, premature aging of skin, dysmorphic facial appearance, and joint abnormalities. It is unlikely, however, that elastin deletions account for all features of WS. Since the deletions responsible for this disorder extend well beyond the elastin locus, we have hypothesized that WS is a contiguous gene disorder (Table 1).

No previously characterized genes except elastin were mapped to this region of chromosome 7q11.23. To rapidly identify new candidate genes for WS, we refined localization of brain cDNAs that were previously assigned to chromosome 7, but none mapped to 7q11.23. We have begun to develop a physical map for the WS region using phage, cosmids, P1s, and YACs. Using these reagents, we are characterizing the size and location of WS-associated deletions. By identifying and characterizing additional genes from this region, we will define mechanisms underlying other WS features, including the specific learning profile and personality.

	Molecular Genetic Studies of LQT Syndrome Reveal Marked Heterogeneity

Top Abstract Introduction SVAS, an Inherited Vascular... Haploinsufficiency of Elastin... Molecular Genetic Studies of... HERG and SCN5A... Clinical Implications Summary References

 
LQT is characterized by syncope, seizures, and sudden death, usually in young, otherwise healthy individuals. Patients with LQT have prolonged QT intervals on ECGs, indicating delayed cardiac repolarization. The clinical features of LQT result from episodic cardiac arrhythmias, specifically ventricular tachyarrhythmias such as torsade de pointes and ventricular fibrillation. Although LQT is not a common diagnosis, repolarization-related arrhythmias are very common. More than 300,000 United States citizens die suddenly every year, and in many cases, the underlying mechanism may be abnormal cardiac repolarization.

After developing a quantitative method for diagnosing LQT by ECG, we discovered tight linkage between autosomal-dominant LQT and a polymorphism at HRAS.^{12 13} This discovery localized an LQT gene to chromosome 11p15.5 and made genetic testing possible in some families. In initial experiments, we found no evidence of recombination between HRAS and LQT. This linkage made HRAS a candidate gene for LQT, a hypothesis supported by the work of other researchers showing that ras proteins modulate cardiac potassium channels.¹⁴ Several months later, however, we completed sequencing the HRAS coding region of several unrelated patients and found no mutations, indicating that the LQT locus was probably nearby but was not HRAS itself. In recent mapping experiments, we confined this LQT gene to a 700- to 900-kb region of chromosome 11.¹⁴ These studies excluded several candidate genes, including HRAS, two potassium channels (KCNA4 and KCNC1), and the D4 dopamine receptor DRD4.

The first seven families that we studied were linked to chromosome 11p15.5, suggesting that autosomal-dominant LQT might be genetically homogeneous.^{11 12} In 1992, however, Benhorin and colleagues¹⁶ reported locus heterogeneity for LQT, a finding that was rapidly confirmed by others, including our group.^{15 16 17} Our laboratory subsequently identified two additional LQT loci, LQT2 on chromosome 7q35-36 and LQT3 on chromosome 3p21-24 (Fig 6).¹⁸ Since several families in our study remain unlinked, at least one more LQT locus exists.

View larger version (34K): [in this window] [in a new window]   Figure 6. Pedigree structure and phenotype of LQT families. Individuals showing the characteristic features of LQT, including prolongation of the QT interval on ECGs and history of syncope, seizures, or aborted sudden death, are indicated by filled circles (females) or squares (males). Unaffected individuals are indicated by open circles or squares. Haplotypes for polymorphic markers linked to LQT2 shown under each individual include (centromere to telomere) D7S505, D7S636, HERG5-11, HERG3-8, and D7S483. Haplotypes cosegregating with the disease phenotype are indicated by a box. Recombination events are indicated with a horizontal black line. Haplotype analyses indicate that the LQT phenotype in these kindred is linked to markers on chromosome 7q35-36.

We have used two strategies to identify and characterize LQT genes: a candidate gene approach and positional cloning. The candidate gene approach relies on likely mechanistic hypotheses based on physiology. Since LQT is associated with abnormal cardiac repolarization, genes that encode ion channels or their gene modulators are likely candidates. We have excluded many candidate genes, including KCNA5, which we cloned and mapped, and other previously characterized potassium channel genes.¹⁹ We have also eliminated specific candidate genes for LQT2 (CLCN1, a chloride channel, and CHRM2, a muscarinic receptor) by linkage analysis using intragenic polymorphisms developed in our laboratory. We also excluded a gene encoding the -1 subunit of a calcium channel (CACNLA2), which was previously mapped to chromosome 3 and is completely linked to LQT3.

	HERG and SCN5A Mutations Cause LQT

Top Abstract Introduction SVAS, an Inherited Vascular... Haploinsufficiency of Elastin... Molecular Genetic Studies of... HERG and SCN5A... Clinical Implications Summary References

 
Recently, we discovered that LQT can be caused by mutations in a putative cardiac potassium channel gene, HERG, and the cardiac sodium channel gene SCN5A (Table 2, Fig 7).^{20 21} Several lines of evidence support these conclusions. First, we used physical and genetic mapping to place HERG and SCN5A in the same chromosomal region as LQT2 and LQT3, respectively. Second, we demonstrated that HERG is strongly expressed in the heart; cardiac expression of SCN5A was already demonstrated. Third, we identified mutations of HERG and SCN5A associated with LQT in families. Many of these mutations were intragenic deletions, but for HERG we also identified several point mutations. One of the HERG point mutations arose de novo and occurred within a highly conserved region encoding the predicted potassium-selective domain of HERG. Finally, the type and location of the mutations identified in HERG and SCN5A make physiological sense. Together, these data indicate that HERG is LQT2 and that SCN5A is LQT3.

View this table: [in this window] [in a new window]   Table 2. Molecular Genetics of Autosomal-Dominant Long-QT Syndrome

View larger version (45K): [in this window] [in a new window]   Figure 7. Schematic of HERG and SCN5A and the location of some LQT-associated mutations. Note that not all amino acids are shown.

We have not yet defined the molecular mechanisms underlying these disorders, but our data suggest possibilities. The function of the protein encoded by HERG is not known, but it has predicted amino acid–sequence homology to potassium channels. HERG was isolated from a hippocampal cDNA library by homology to the Drosophila ether a-go-go gene (eag), which encodes a calcium-modulated potassium channel.^{22 23} HERG is not the human homologue of eag, however; it shares only 50% amino acid–sequence homology. Potassium channels are formed from four subunits,²⁴ either as homotetramers or heterotetramers.²⁵ These observations suggest that combinations of normal and mutant HERG -1 subunits could form abnormal HERG channels, raising the possibility that HERG mutations have a dominant-negative effect on cardiac potassium channel function. The mutations that we identified in HERG are consistent with this hypothesis, suggesting that chromosome 7–linked LQT results from nonfunctional cardiac potassium channels and reduced repolarizing current (Fig 8).

View larger version (65K): [in this window] [in a new window]   Figure 8. Schematic showing hypothesized molecular mechanism of chromosome 7–linked LQT: dominant-negative mutations of HERG reduce myocellular repolarizing currents. Interaction of mutant with normal HERG monomers leads to abnormal HERG channels (tetramers).

By contrast, in chromosome 3–linked LQT the LQT-associated deletions identified in SCN5A are likely to result in functional cardiac sodium channels with altered properties, such as delayed inactivation or voltage dependence of channel inactivation. It is unlikely that more deleterious mutations of SCN5A will cause LQT. A reduction of the total number of cardiac sodium channels, for example, would be expected to reduce action potential duration, a phenotype opposite that of LQT. The mutations we identified cause the deletion of three amino acids, KPQ, in the cytoplasmic linker between DIII and DIV. The KPQ sequence is highly conserved. This region is of known importance for fast inactivation, suggesting that LQT-associated SCN5A mutations reduce or eliminate fast inactivation of the cardiac sodium channel, thereby prolonging depolarizing currents (Fig 9).^{26 27}

View larger version (22K): [in this window] [in a new window]   Figure 9. Graphs (top) and schematics (bottom) showing hypothesized mechanism of chromosome 3–linked LQT: subtle mutations of SCN5A result in continued depolarizing currents during myocellular repolarization.

Our data have implications for the mechanisms of arrhythmia in LQT. Two hypotheses have been proposed.²⁸ One suggests that a predominance of left autonomic innervation causes abnormal cardiac repolarization and arrhythmias. The second hypothesis suggests that mutations in cardiac-specific ion channel genes or in genes that modulate cardiac ion channels cause delayed myocellular repolarization. Delayed myocellular repolarization could promote reactivation of L-type calcium channels, resulting in secondary depolarizations,^{29 30} the likely cellular mechanisms of torsade de pointes arrhythmias. The discovery that two forms of LQT result from mutations in cardiac potassium and sodium channel genes supports the myocellular hypothesis.

	Clinical Implications

Top Abstract Introduction SVAS, an Inherited Vascular... Haploinsufficiency of Elastin... Molecular Genetic Studies of... HERG and SCN5A... Clinical Implications Summary References

 
The diagnosis of LQT has been based on a history of syncope, sudden death, and congenital deafness, a family history of LQT, and ECG findings. The latter include prolongation of the QT interval corrected for heart rate (the QT interval divided by the square root of the RR interval or the QT_c).³¹ In the past, a QT_c of >0.44 second was used to define QT prolongation; however, this is probably not an adequate diagnostic determination. T-wave abnormalities such as T-wave alternans have also been described in association with LQT, but these abnormalities are not a constant feature of LQT and are difficult to quantify. Stress electrocardiography is becoming increasingly important in the diagnosis of LQT. Preliminary data suggest that the QT interval fails to shorten appropriately in response to increased heart rate in LQT patients.

We have used molecular diagnosis of LQT in families to help define its clinical spectrum.³² In the (chromosome 11–linked) families that we have studied, 63% of the LQT gene carriers have had at least one syncopal episode; 37% have never had syncope. Of noncarriers, 7% have a history of syncope. Only 5% of the gene carriers had a history of aborted sudden death. This number underestimates the risk of sudden death in this population because we were unable to determine the gene-carrier status of individuals who died before the study. Even if we assume that everyone who died suddenly in this family was a gene carrier, the incidence of sudden death would be <1% per year. The age of onset of symptoms in LQT gene carriers was a mean of 8 in males and 14 in females. The sexes were evenly represented in the symptomatic group.

We have also examined the ECG findings of LQT gene carriers.³² As expected, the ECG was neither completely sensitive nor specific for diagnosis of LQT. While the mean QT_c for gene carriers at 0.49 second was longer than that for noncarriers at 0.42 second, 63% of the population had overlapping QT_cs of 0.41 to 0.47 second. Diagnosis of LQT using a cutoff of 0.44 second therefore led to misclassifications. In our study, 5% of LQT gene carriers were falsely classified as normal, whereas 15% of noncarriers were misclassified as affected. Among gene carriers, the range of static QT_cs was similar to that for noncarriers and was not useful for predicting risk for symptoms. Therefore, it is clear that other clinical or genetic tools must be used for presymptomatic diagnosis. Nevertheless, the ECG was helpful at the extremes, and a QT_c of >0.47 second was completely predictive for gene carriers, whereas a QT_c of <0.41 second was completely predictive for noncarriers.

Molecular genetic tests offer the promise of improved diagnosis of LQT. Continued mutational analyses of LQT2 and LQT3 will facilitate genetic testing for these forms of LQT, whereas identification of genes responsible for the chromosome 11–linked and other forms of LQT leads to the development of generalized diagnostic tests. Improved diagnostic capacity and better mechanistic understanding may enable rational therapy.

	Summary

Top Abstract Introduction SVAS, an Inherited Vascular... Haploinsufficiency of Elastin... Molecular Genetic Studies of... HERG and SCN5A... Clinical Implications Summary References

 
We used molecular genetics to identify genes responsible for autosomal-dominant SVAS (the elastin gene) and two forms of LQT (putative cardiac potassium and sodium channel genes HERG and SCN5A, respectively). Each of these discoveries has led to improved mechanistic understanding of the disorder and created the possibility for genetic testing. We have developed a simple and sensitive cytogenetic test for diagnosis of WS, fluorescence in situ hybridization with probes at the elastin locus. This test is now available in many medical centers and can be used for early diagnosis. We are working to develop genetic tests for autosomal-dominant SVAS and LQT, but this will require identification of additional mutations and additional LQT genes and development of a simple and accurate assay (probably hybridization of patient DNA to silicon chip containing DNA sequence complementary to known mutations). Specialized research laboratories such as ours can provide genetic testing for many families, but these tests are not yet generally available. These tests may be particularly useful for LQT families, since asymptomatic LQT gene carriers are still at risk for sudden death. Finally, molecular genetic and physiological studies offer the possibility of new strategies for treatment and prevention of cardiovascular disease.

	Acknowledgments

 
The work described here was supported by the American Heart Association, March of Dimes, and National Heart, Lung, and Blood Institute grants RO1-HL-50343 and RO1-HL-46401.

Received April 11, 1995; revision received May 10, 1995; accepted May 17, 1995.

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Top Abstract Introduction SVAS, an Inherited Vascular... Haploinsufficiency of Elastin... Molecular Genetic Studies of... HERG and SCN5A... Clinical Implications Summary References

 
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