Genotype-Phenotype Correlates in Long-QT Syndrome

The emergence of specific genotype/phenotype associations in LQTS suggest relatively gene-specific triggers, ECG patterns, and response to therapy (Fig. 32-3). Swimming- and exertion-induced cardiac events are strongly associated with mutations in KCNQ1 (LQT1), whereas auditory triggers and events occurring during the postpartum period most often occur in patients with LQT2. Whereas exertion- or emotional stress–induced events are most common in LQT1, events occurring during periods of sleep or rest are most common in LQT3. In a study population of 721 LQT1 and 634 LQT2 genetically confirmed patients from the U.S. portion of the international LQTS registry, a multivariate analysis was used to assess the independent contribution of clinical and mutation-specific factors to the occurrence of a first triggered event associated with exercise, arousal, or sleep/rest.^14,15 Among the 221 symptomatic LQT1 patients, the first cardiac event was most often associated with exercise (55%), followed by sleep/rest (21%), arousal (14%), and nonspecific (10%) triggers; in contrast, the 204 symptomatic LQT2 patients most often had their first event associated with either arousal triggers (44%) or nonexercise/nonarousal triggers (43%), and only 13% of the symptomatic LQT2 patients had an exercise-triggered first event. In addition, males younger than 13 years with LQT1 had a nearly 3-fold increase in risk for exercise-triggered events, whereas females 13 years or older with LQT1 had a 3.5-fold increase in risk for sleep/rest nonarousal events. For LQT2 patients, the rate of arousal-triggered events was similar between boys and girls, but the rate of arousal-triggered events was significantly higher in women than in men (26% versus 6% at 40 years of age) after the onset of adolescence. Characteristic gene-suggestive ECG patterns have been described previously. LQT1 is associated with a broad-based T wave, LQT2 with a low-amplitude notched or biphasic T wave, and LQT3 with a long isoelectric segment followed by a narrow-based T wave.

However, exceptions to these relatively gene-specific T wave patterns exist, and thus due caution must be exercised when making a pre–genetic test prediction of the particular LQTS subtype involved because the most common clinical mimicker of an LQT3-appearing ECG is seen in patients with LQT1. This is key to keep in mind because importantly, the underlying genetic basis heavily influences the response to standard LQTS pharmacotherapy (beta blockers), with beta blockers being extremely protective in LQT1 patients and moderately protective in patients with LQT2 and LQT3.¹⁶ Additionally, targeting the pathologic LQT3-associated late sodium current with agents such as mexiletine, flecainide, or ranolazine may represent a gene-specific therapeutic option for LQT3.^17,18 Attenuation in repolarization with clinically apparent shortening of the QTc has been demonstrated with such a strategy, although no evidence-based survival benefit has been shown thus far.¹⁸ Realistically, however, at least a 30-year study may be needed for the latter. Even though the generalization that beta blocker efficacy depends on the genotype has been well accepted, the effectiveness of beta blocker therapy may be largely trigger-specific rather than dependent on genotype. In patients with either LQT1 or LQT2, beta blockade was associated with a pronounced 71% (LQT2 patients) to 78% (LQT1 patients) reduction in the risk for exercise-triggered cardiac events but had no statistically significant effect on the apparent risk for arousal- or sleep/rest-triggered events.^4,15 However, it should be noted that many symptomatic LQT1 and LQT2 patients experience a subsequent cardiac event associated with a different trigger. For example, an LQT2 patient first experiencing an arousal event or one during sleep may subsequently have an exercise-triggered event. Therefore, beta blocker therapy still remains first-line therapy even for patients experiencing a non–exercise-associated first event.

In addition, intragenotype risk stratification has been completed for the two most common subtypes of LQTS based on mutation type, mutation location, and cellular function.^19–22 Patients with LQT1 secondary to K_v7.1 missense mutations localizing to the transmembrane-spanning domains clinically have a twofold greater risk for an LQT1-triggered cardiac event than do LQT1 patients with mutations localizing to the C-terminal region. In addition, missense mutations localizing to the so-called cytoplasmic loops (C-loops) within the transmembrane-spanning domains, an area of the protein involved in the regulation of adrenergic channels, are associated with the highest rate of both exercise- and arousal-triggered events but not with an increase rate of sleep/rest-associated events.¹⁵ C-loop K_v7.1 missense mutations were consistently associated with greater than a sixfold increase in risk for exercise-triggered events in comparison to nonmissense mutations and an almost threefold increase in comparison to N- and C-terminal missense mutations.¹⁵

Patients with mutations resulting in a greater degree of K_v7.1 loss of function at the cellular in vitro level (i.e., dominant negative) have a twofold greater clinical risk than that of patients with mutations that damage the biology of the K_v7.1 channel less severely (haploinsufficiency). Adding to the traditional clinical risk factors, molecular location and cellular function are independent risk factors used in the evaluation of patients with LQTS.²⁰ Akin to molecular risk stratification in LQT1, patients with LQT2 secondary to K_v11.1 pore region mutations have a longer QTc and more severe clinical manifestation of the disorder and experience significantly more arrhythmia-related cardiac events occurring at a younger age than do LQT2 patients with non–pore-related mutations in K_v11.1.²³ Similarly, in a Japanese cohort of LQT2 patients, those with pore mutations had a longer QTc, and although not significant among probands, nonprobands with pore mutations experienced their first cardiac event at an earlier age than did those with a non–pore-related mutation.²¹ Most recently, additional information has been gleaned suggesting that LQT2 patients with mutations involving the transmembrane pore region had the greatest risk for cardiac events, those with frameshift/nonsense mutations in any region had intermediate risk, and those with missense mutations in the C-terminus had the lowest risk for cardiac events.²² Interestingly, LQT2 patients with mutations in the pore loop region of the K_v11.1 channel have a greater than twofold increased risk for arousal-triggered events, and LQT2 patients with non–pore loop transmembrane region mutations have an almost sevenfold increase in the risk for exercise-triggered cardiac events over patients with N-terminal/C-terminal (non-PAS domain) mutations.²⁴

Incomplete penetrance and variable expressivity are the clinical hallmark features of LQTS, and it has long been thought that co-inheritance of a true disease-causing mutation and either a common or rare channel genetic variant may determine the expressed severity of the disorder. For example, coexistence of the common K897T-KCNH2 polymorphism and the A1116V-KCNH2 mutation (on opposite alleles) led to a more severe clinical course in a single Italian LQTS family. The A1116V mutation by itself produced a subclinical phenotype of mild QT prolongation and an asymptomatic course, whereas the proband hosting both variants had clinically overt disease consisting of diagnostic QT prolongation, presyncope episodes, and cardiac arrest.²⁵ Besides cardiac ion channels, single nucleotide polymorphisms (SNPs) of non–ion channel genes such as NOS1AP (the gene encoding the nitric oxide synthase 1 adapter protein), ADRA2C (alpha_2C-adrenergic receptor), and ADRB1 (beta₁-adrenergic receptor) may modify disease severity in LQTS.^26–29

In 2012, Amin and colleagues provided compelling evidence for a strong disease-modifying effect of a 3′ untranslated region (3′UTR), KCNQ1 allele–specific haplotype in LQT1 mutation–positive pedigrees; the magnitude of the effect on the QTc and symptomatology goes well beyond any other currently described genetic modifiers.³⁰ The KCNQ1 gene encodes for a single K_v7.1 ion channel alpha subunit. Following KCNQ1 gene expression and post-translational modifications, four alpha subunits are assembled to create a pore-forming K_v7.1 tetrameric channel. Therefore, if a patient had a heterozygous KCNQ1 mutation (i.e., one normal KCNQ1 gene allele and one mutant allele), one would expect that if both the normal and mutant gene alleles were expressed in equal amounts, of the channels would be normal homomeric tetramers and would be mutant homomeric tetramers. The remaining channels would be hybrids containing both normal and mutant alpha subunits. One would predict that if the normal KCNQ1 gene allele expression was somehow suppressed, there would be relatively more KCNQ1 mutant alpha subunits translated and ultimately assembled to provide more dysfunctional KCNQ1 channels and thus lead to a more severe manifestation of the disorder (Fig. 32-4). Simply put, far more bad (mutant) channels than good (healthy) channels would be created. The opposite would be true if the mutation containing the KCNQ1 allele were suppressed.

Most genes have a 3′UTR that produces an mRNA transcript that contains regions of cis-regulatory binding sites for small noncoding microRNA (miRNA) molecules that bind to the transcript and ultimately inhibit that gene’s expression. Naturally occurring genetic variation within these 3′UTRs (miR-SNPs) can either abolish existing or create new miRNA binding sites. Amin and colleagues identified three naturally occurring SNPs (rs2519184, rs8234, and rs10798) within the KCNQ1 3′UTR whereby the presence of their minor alleles (A, G, G) generates a “suppressive” haplotype by creating new miRNA binding sites that suppress expression of the KCNQ1 gene allele in which they reside.³⁰ In a cohort of 168 KCNQ1 (LQT1) mutation–positive individuals from 41 families, Amin and colleagues showed that inheritance of the “suppressive” haplotype residing on the normal “healthy” allele produced a more severe LQT1 phenotype with regard to QTc and symptomatology than did inheritance of the “suppressive” haplotype residing on the same allele as the KCNQ1 mutation (shorter QTc and fewer symptoms).³⁰ This intriguing discovery may not only explain a significant component of the reduced penetrance and variable expressivity that is a common feature of arrhythmia syndromes but may also represent a paradigm shift in our thinking about disease-modifying genetic drivers of mendelian disorders because one of the most important genetic determinants of disease severity in LQT1 appears to be the 3′UTR KCNQ1 haplotype on the allele inherited from the unaffected “non-LQTS” parent.

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