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American Journal of Critical Care. 2007;16: 416-412
Copyright © 2007 by the American Association of Critical-Care Nurses.
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Cases of Note features peer-reviewed case reports and case series that document clinically relevant findings from critical and high acuity care environments. Cases that illuminate clinical diagnoses and management issues in the treatment of critically and acutely ill patients and include discussion of the patient’s experience with the illness or intervention are encouraged. Proposals for future Cases of Note articles may be e-mailed to ajcc{at}aacn.org.

Neonatal Long QT Syndrome Due to a De Novo Dominant Negative hERG Mutation

By Theresa A. Beery, RN, PhD, ACNP, Kerry A. Shooner, MS, CGC and D. Woodrow Benson, MD, PhD. Theresa A. Beery is an associate professor at the University of Cincinnati, Cincinnati, Ohio. D.Woodrow Benson is the director of cardiovascular genetics and Kerry A. Shooner is a genetic counselor at Cincinnati Children’s Hospital Medical Center, University of Cincinnati.

Corresponding author: Theresa A. Beery, RN, PhD, ACNP, Associate Professor, University of Cincinnati, PO Box 210038, Cincinnati, OH 45221-0038 (e-mail: theresa.beery{at}uc.edu).


   Abstract
Top
 Abstract
Case Report
 Molecular Genetic Studies
 Long-term Follow-up
 Discussion
 Conclusion
 References
 
A 4-day-old girl with ventricular tachyarrhythmias, sinus bradycardia, and 2:1 atrioventricular block had prolongation of the QT interval. She was symptomatic with arching, gasping, and cyanosis presumably due to a life-threatening ventricular tachyarrhythmia such as torsades de pointes. Molecular genetic studies indicated a heterozygous, de novo, dominant negative mutation in hERG, a gene that encodes a protein in a potassium ion channel. The parents do not have the mutation. The patient’s clinical scenario was produced by the convergence of 3 events: a de novo mutation occurred in hERG, the mutation was dominant negative, and the action of the mutation resulted in neonatal long QT syndrome. The child was treated aggressively and is doing well at age 6 years.

Congenital long QT syndrome (LQTS) is an inherited group of abnormalities caused by mutations in ion channels that result in prolonged ventricular repolarization. Persons with the syndrome have a propensity for life-threatening ventricular tachyarrhythmias (eg, torsades de pointes) that can lead to syncope and sudden death.1,2 Mutation of single copies (heterozygous) of genes that code for cardiac potassium and sodium channels cause most cases of LQTS. KCNQ1 (also known as KVLQT1) and KCNH2 (also known as hERG) are the genes most commonly affected; together, mutations in these genes account for approximately 95% of cases.3 Congenital LQTS without concurrent deafness is Romano-Ward syndrome (autosomal dominant inheritance). Congenital LQTS with profound sensorineural deafness is indicative of Jervell and Lange-Nielsen syndrome (autosomal recessive inheritance).

In some patients, LQTS is identified only by a prolonged QT interval on a 12-lead electrocardiogram (ECG), but additional criteria including positive family history, occurrence of symptoms associated with the syndrome, and documentation of tachyarrhythmia have been used to increase the likelihood of a clinically accurate diagnosis.1–4 One-third of patients with LQTS have no family history of the syndrome; such isolated cases suggest either the sporadic occurrence of a new mutation or reduced penetrance.5–7 (If a disease-causing mutation has reduced penetrance, some individuals with the mutation [ie, the genotype] do not manifest the traits or evidence of the disease [ie, the phenotype]). In LQTS, reduced penetrance is common and may be as low as 25%8; in such cases, genetic testing may reveal that a number of family members are asymptomatic but have the mutation. The incidence of true de novo mutations in genes associated with LQTS is difficult to assess, but it appears to be low; de novo mutations have been reported in only 4 patients who had mutations in either the sodium channel gene SCN5A or the potassium channel gene hERG.5–7,9


Congenital long QT syndrome, caused by cardiac ion channel mutations, results in prolonged ventricular repolarization.

 

Although LQTS is termed congenital, the mean age of patients with the syndrome at the time of diagnosis is approximately 30 years.2 Manifestation of LQTS during the first year of life is relatively uncommon; it has been documented in only 4% of cases.2,10–12 Prenatal or neonatal LQTS is often diagnosed in conjunction with sinus bradycardia and/or 2:1 atrioventricular block11–14; patients with such severe effects are often homozygotes (ie, have 2 identical mutations) or compound heterozygotes (ie, have inherited 2 different mutations, 1 from each parent).12,15–18 Among patients with prenatal or neonatal manifestations of LQTS, 50% die before the age of 6 months.19,20

We report the case of a patient with neonatal LQTS. Because of the early manifestation of the syndrome and the severe phenotype, we expected to find a homozygous mutation or compound heterozygous mutations. The first possibility (homozygous mutation) seemed unlikely because the parents denied being blood relatives.


   Case Report
Top
 Abstract
 Case Report
Molecular Genetic Studies
 Long-term Follow-up
 Discussion
 Conclusion
 References
 
The proband (ie, the patient) was an apparently healthy newborn girl of European descent; her mother had had excellent prenatal care and an uncomplicated labor and delivery. At the age of 4 days, the infant had a sudden onset of choking, gasping, and cyanosis at home, and she was taken to the emergency department. The results of a cardiac examination and an echocardiogram were normal, but an ECG showed a substantially lengthened corrected QT interval (QTc) of 637 milliseconds. The QTc reflects the QT interval after the interval is mathematically normalized for heart rate; most commonly the Bazett formula is used. In a study21 of 3946 newborns, the mean QTc on the fourth day of life was 397 milliseconds (SD, 18 milliseconds), and QT prolongation was defined as a QTc longer than 451 milliseconds on the fourth day of life.

The diagnosis for our patient was neonatal LQTS. Physicians’ reports noted episodes of ventricular tachyarrhythmia (data not available), sinus bradycardia (Figure 1AGo), and second degree atrioventricular block (Figure 1BGo) at that time. During 21/2 weeks of hospitalization, she experienced second degree atrioventricular block with a 2:1 conduction pattern when her heart rate was greater than 150/min and first degree atrioventricular block with 1:1 conduction at slower atrial rates. The QTc was persistently prolonged.


Figure 1
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  		Figure 1 Electrocardiograms of the patient during the neonatal period show sinus bradycardia (A) and second degree atrioventricular block (B).

 
Because of the diagnosis of neonatal LQTS and the potential for a grave outcome, the patient was treated aggressively. A dual-chamber pacemaker was placed, and ß-blocker therapy was started. Propranolol was used for maintenance. Her subsequent clinical course has been excellent, with no episodes suggestive of ventricular arrhythmia.

An ambulatory ECG when she was 3 years old showed predominantly sinus rhythm with a QTc of 531 milliseconds. Rarely, ventricular pacing occurred at a lower ventricular rate of 60/min with complete ventricular sensing and capture. The patient was asymptomatic with atenolol and labetalol treatment. When she was 5 years old, interrogation of the pacemaker indicated ventricular pacing only 0.3% of the time, so the device was turned off. Six months later, the device was removed after findings on an ambulatory ECG were normal. The patient has been event-free during the 6 months after removal of the pacemaker.

The patient’s family members had no history of cardiac disease, seizures, pregnancy loss, neonatal death, or sudden cardiac death (Figure 2Go). Consanguinity was denied. The ECG findings for both the mother and the father were normal (father’s QTc 430 milliseconds; mother’s QTc 410 milliseconds). The parents were advised to consider genetic testing to understand potential risks for themselves and for future children.


Figure 2
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  		Figure 2 Pedigree of the patient’s family. The proband (index patient; arrowhead) is reportedly the only affected person in this family.

 

   Molecular Genetic Studies
Top
 Abstract
 Case Report
 Molecular Genetic Studies
Long-term Follow-up
 Discussion
 Conclusion
 References
 
Polymerase chain reaction was used to amplify the coding regions and splice sites of each LQTS candidate gene (KCNQ1, hERG, SCN5A, KCNE1, KCNE2) for both the parents and the proband. The products of the reaction were prepared and sequenced by using a DNA analyzer (ABI PRISM 3700, Applied Biosystems, Foster City, California). Allele-specific oligonucleotide hybridization was used to confirm the results of DNA sequencing. Amplified DNA was hybridized with oligonucleotides that were 17 base pairs long, labeled with phosphorus 32, and contained either the mutant or the wild-type sequence.22

During systematic survey of the candidate genes, a single, heterozygous nucleotide substitution (cytosine at nucleotide 1682 replaced by thymine; 1682C>T) in hERG was detected in the patient’s DNA. This missense point mutation involves a change in a single DNA base, from cytosine to thymine, in the hERG gene at position 1682. This sequence alteration resulted in a non-synonymous change in the amino acid at position 561, from alanine to valine (A561V; Figure 3Go). In the {alpha}-protein subunit of the rapidly activating delayed rectifier potassium channel, alanine at position 561—which is located in the S5 trans-membrane domain of the protein hERG—previously has been identified as a cause of LQTS and has a dominant negative action.23,24 Neither parent had this mutation (1682C>T), and no additional sequence variations were found. These results were confirmed by using allele-specific oligonucleotide hybridization.


Figure 3
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  		Figure 3 Sequence electropherogram indicates the point mutation found in the patient, which resulted in an amino acid change from alanine (Ala) to valine (Val).

 

   Long-term Follow-up
Top
 Abstract
 Case Report
 Molecular Genetic Studies
 Long-term Follow-up
Discussion
 Conclusion
 References
 
Because of the patient’s ongoing risk for cardiac events, her elementary school has made emergency care easily accessible. Two automatic external defibrillators have been purchased, and training in their use has been provided for all teachers. Before the genetic testing, the physician counseled against participation in competitive sports, such as soccer, but approved of gymnastics in accordance with the American Heart Association recommendations25 for physical activity and participation in recreational sports for young patients with genetic cardiovascular disease. The patient’s family provided the gymnastics coach with information from the Sudden Arrhythmic Death Syndrome Foundation targeted to athletic coaches.26


   Discussion
Top
 Abstract
 Case Report
 Molecular Genetic Studies
 Long-term Follow-up
 Discussion
Conclusion
 References
 
The gene hERG encodes the protein Kv11.1, the {alpha}-subunit of the cardiac rapidly activating delayed rectifier potassium channel.20,24 Heterozygous mutations account for up to 45% of cases of LQTS, specifically the LQT2 form. Associated ventricular arrhythmias are triggered minimally with exercise but markedly with loud auditory stimuli.4


Neonates with the longest QT intervals and/or 2:1 AV block are at the highest risk for having a cardiac event.

 

Identification of mutations and their functional characterization have contributed greatly to our understanding of the pathogenesis of abnormalities due to DNA sequence variations. Mutations in hERG can cause disruption in the synthesis or permeability/gating of ion channels; they also can lead to trafficking defects or to the location of nonfunctional channels at the cell surface.15,27 Loss of function is the most common mechanism for the nearly 200 reported hERG mutations; that is, a significant reduction or complete loss of the protein product encoded by the mutated allele (the altered form of the gene) results.28 Fewer than 20 reported heterozygous mutations have a dominant negative action, so termed because the protein product from the single mutant allele disables the product from the normal (wild type) allele.16,23,24 Instead of missing 50% of the desired product as a result of the loss of one mutation in the heterozygote, almost no usable product is formed, making the heterozygote equivalent to an hERG "knockout" (having both copies of the gene disabled). In contrast, gain-of-function mutations can result in the short QT syndrome.29


   Conclusion
Top
 Abstract
 Case Report
 Molecular Genetic Studies
 Long-term Follow-up
 Discussion
 Conclusion
References
 
The major finding in this case is the unusual coming together of 3 events: a single de novo mutation occurred, the mutation had dominant negative effects, and the effects led to neonatal LQTS. The mutation is located in hERG (or KCNH2), the gene that encodes a potassium ion channel. The hERG mutation (1682C>T) in this patient produces a defect (A561V) in the protein Kv11.1, leading to retention of the potassium ion channels in the endoplasmic reticulum.15,27,30 Because the defective protein suppresses trafficking of wild-type channels, the mutation has a dominant negative effect. Therefore, a dominant negative mechanism, rather than our hypothesized compound heterozygosity, is the most likely cause of the severe phenotype of this patient.

The child had neonatal LQTS and experienced events (gasping, arching, cyanosis) suggestive of low cardiac output due to a tachyarrhythmia such as torsades de pointes. Lupoglazoff et al11 reported that hERG mutations occur more often in children with 2:1 atrioventricular block, whereas mutations in KCNQ1 are more common in patients with sinus bradycardia. The authors11 also suggest that mutations in KCNQ1 are more often associated with good outcomes. Neonates with the longest QT intervals (QTc >600 milliseconds) and/or 2:1 atrioventricular block are at the highest risk for a cardiac event.

Our patient with a dominant negative hERG mutation, second degree block, and a QTc of 637 milliseconds had significant risk for a poor outcome. This case illustrates the importance of obtaining a thorough family history at the time of initial assessment to identify possible genetic risk. If genetic risk is suggested by a family’s pedigree, clinicians must know when and how to make a referral to genetics specialists, including counselors. Despite no cases suggestive of LQTS in this child’s family, her parents were concerned about the genetic risk for future offspring, making genetics referral an important part of the care.


   ACKNOWLEDGMENTS
 
This research was performed at Cincinnati Children’s Hospital Medical Center and the University of Cincinnati.

To purchase electronic or print reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints{at}aacn.org.

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FINANCIAL DISCLOSURES
This study was funded by grant 5K23NR008716 from the National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland.


   REFERENCES
Top
 Abstract
 Case Report
 Molecular Genetic Studies
 Long-term Follow-up
 Discussion
 Conclusion
 References
 

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