In 1957, Jervell and Lange-Nielsen reported a syndrome of congenitalsensory deafness associated with a prolonged QT interval infour children of a Norwegian family.1 The affected childrenhad multiple syncopal episodes, and three died suddenly at theages of four, five, and nine years. Since 1957, other examplesof the long-QT syndrome associated with deafness (the Jervelland Lange-Nielsen syndrome) have been described.2,3,4 In allcases, the apparent mode of inheritance was autosomal recessive.This syndrome is rare (estimated incidence, 1.6 to 6 cases permillion).2 Affected persons are susceptible to recurrent syncope,and they have a high incidence of sudden death and short lifeexpectancy. Syncope results from torsade de pointes ventriculartachycardia and ventricular fibrillation.5,6
The Romano–Ward syndrome is an autosomal dominant formof the long-QT syndrome and is not associated with deafnessor other phenotypic abnormalities.7,8 The incidence of the Romano–Wardsyndrome is higher than that of the Jervell and Lange-Nielsensyndrome, but affected persons generally have milder symptoms.9,10
In previous studies, we mapped the genes for the autosomal dominantlong-QT syndrome to chromosomes 11p15.5 (LQT1), 7q35–36(LQT2), and 3p21–24 (LQT3).11,12,13 A fourth gene (LQT4)was mapped to chromosome 4q25–27.14 We subsequently identifiedgenes for LQT1 (KVLQT1), LQT2 (HERG), and LQT3 (SCN5A).15,16,17,18These genes encode cardiac ion channels and support the hypothesisthat the long-QT syndrome results from delayed myocellular repolarization.Functional expression of KVLQT1 in xenopus oocytes and mammaliancells induces a potassium current unlike any known cardiac current.In recent experiments, we and others demonstrated that the KVLQT1protein joins with another protein known as minimal potassium-channelsubunit (minK) to form a cardiac potassium channel expressingthe cardiac slow delayed rectifier potassium current (IKs),a channel that contributes to myocellular repolarization.19,20
In this study, we hypothesized that the Jervell and Lange-Nielsensyndrome results from mutations that affect both alleles ofan autosomal dominant gene for the long-QT syndrome. We discoveredthat a patient with the Jervell and Lange-Nielsen syndrome hada homozygous mutation of KVLQT1. Other family members also hadprolongation of the QT interval corrected for heart rate (QTc)with an autosomal dominant pattern of inheritance, but theyhad normal hearing and were heterozygotes. These data indicatethat homozygous mutation of KVLQT1 causes the Jervell and Lange-Nielsensyndrome.
Methods
Ascertainment and Phenotyping of the Kindred
A patient with the Jervell and Lange-Nielsen syndrome was referredto us. A team of researchers attended a large family gatheringorganized by the patient's paternal aunt and grandmother. Informationon the pedigree and the patient's history was collected at thegathering, and electrocardiograms and blood samples were obtained.
The members of the family ranged in age from 13 months to 82years. Each subject was characterized phenotypically on thebasis of the QTc and the presence of symptoms as described.11,13,21Subjects were classified as phenotypically affected by the long-QTsyndrome if they had symptoms (syncope, seizures, or abortedsudden death) and QTc intervals of 0.45 sec1/2 or more or wereasymptomatic with QTc intervals of 0.47 sec1/2 or more. Subjectswere classified as unaffected if they were asymptomatic andhad QTc intervals of 0.41 sec1/2 or less. The status of asymptomaticpersons with QTc intervals of between 0.42 and 0.46 sec1/2 andsymptomatic persons with QTc intervals of less than 0.45 sec1/2was classified as uncertain. The criteria for the assignmentof phenotypes were not age-dependent. Informed consent was obtainedfrom all the subjects or their guardians. The research protocolwas reviewed and approved by the appropriate institutional reviewboards. Phenotypic data were interpreted by investigators whodid not know the patients' genotypes.
Linkage Analysis
Linkage analysis is a technique that can be used to determinewhether a gene responsible for a phenotype is located on thesame chromosomal segment as a genetic marker. With this technique,an investigator examines a family to determine whether a phenotypeis inherited with a specific DNA-sequence variant (allele) ofknown chromosomal location. Genes or segments of DNA that havetwo or more forms are known as polymorphic markers and can bedetected with the polymerase chain reaction (PCR).22
In this study, we used linkage analysis to determine whetherthe phenotype of the long-QT syndrome was inherited with thepolymorphic markers TH and D11S1318, which are located nearKVLQT1.17 Small, synthetic DNA primers (oligonucleotides) wereused to amplify DNA from each subject by PCR. The reactionswere completed with 75 ng of DNA in a final volume of 10 µlwith a thermocycler (model 9600, Perkin–Elmer Cetus).The amplification conditions were as follows: 94°C for 3minutes, followed by 30 cycles of 94°C for 10 seconds, 58°Cfor 20 seconds, and 72°C for 20 seconds. Ten microlitersof 95 percent formamide loading dye was added to each reaction,and the samples were denatured at 94°C for 5 minutes andplaced on ice. Three microliters of each sample was separatedon 6 percent denaturing polyacrylamide gels. The gels were driedon 3MM filter paper (Whatman, Clifton, N.J.) and exposed tofilm for 12 hours at -70°C. The pattern of the alleles ineach subject (the genotype), which appears as bands of variablesize on the film, was determined by inspection.
The genotypes were scored without knowledge of the phenotypicdata and were entered into a computerized relational data base.The likelihood of odds (lod score) for linkage was determinedwith the Linkage version 5.1 software package.23 Penetrancewas assumed to be 95 percent, and the frequency of the genefor the long-QT syndrome (0.001) was assumed to be the samein male and female subjects. The allelic frequencies were setto 1/n, where n equals the number of alleles for each markerin this family (TH, 5 alleles; KVLQT1, 2 alleles; D11S1318,10 alleles).
Mutation Analysis
Single-strand conformation polymorphism (SSCP) analysis wasused to screen for mutations in KVLQT1.15 With this techniquea small (approximately 200-bp) section of a patient's genomicDNA is amplified by PCR. If the patient has a mutation, boththe normal and the mutant alleles are amplified. The two productscan then be separated on nondenaturing gels and distinguished.The principle underlying SSCP analysis is that a single strandof DNA migrates through a nondenaturing gel at a rate dependenton the size and the specific sequence of the strand.24 Anotherstrand identical in size that contains a substitution of a singlenucleotide will travel through the same gel at a slightly differentrate. The difference in mobility results from an altered conformationin the DNA molecule that has the nucleotide substitution, andan abnormal SSCP band is produced.
PCR was completed with 75 ng of DNA in a volume of 10 µlwith a thermocycler (model 9600, Perkin–Elmer Cetus).The amplification conditions were as follows: 94°C for 3minutes, followed by 5 cycles of 94°C for 10 seconds, 64°Cfor 20 seconds, and 72°C for 20 seconds and 30 cycles of94°C for 10 seconds, 60°C for 20 seconds, and 72°Cfor 20 seconds. The reaction mixtures were diluted with 40 µlof 0.1 percent sodium dodecyl sulfate and 10 mM EDTA and with30 µl of 95 percent formamide loading dye. The mixturewas denatured at 94°C for 5 minutes and placed on ice. Threemicroliters of each sample was separated on 5 percent and 10percent nondenaturing polyacrylamide gels (acrylamide:bisacrylamide,49:1) at 4°C and on 0.5x and 1x Mutation Detection Enhancementgels (MDE, FMC BioProducts, Rockland, Me.) at room temperature.Electrophoresis of the 5 percent and 10 percent gels was completedat 40 W for three to five hours; electrophoresis of the 0.5xand 1x MDE gels was completed overnight at 350 V and 600 V,respectively. The gels were dried on 3MM filter paper and exposedto film for 18 hours at -70°C.
DNA-Sequence Analysis
SSCP bands were cut out of the gel and eluted in 100 µlof double-distilled water at 65°C for 30 minutes. Ten microlitersof eluted DNA was used as a template in a second PCR reactionwith the original primer pair. The products were separated on1 percent low-melting-temperature agarose gels (FMC BioProducts),extracted with phenol–chloroform, and precipitated inethanol. DNA was sequenced in both directions by the dideoxychain-termination method with a DNA sequencer (model 373A, AppliedBiosystems).
Results
Phenotypic Characteristics
We studied a family of Scottish descent in which one child hadthe Jervell and Lange-Nielsen syndrome. This female infant (PatientV-5, Figure 1) was born to a consanguineous marriage of secondcousins. At 35 weeks' gestation, the obstetrician informed the25-year-old mother that the fetal heart rate had dropped to70 to 80 beats per minute. An ultrasound study showed normalgrowth and development, with a heart rate of 80 and a regularrhythm. At 38 weeks the heart rate continued to be slow. A secondultrasound study confirmed normal development, bradycardia,and regular rhythm. The infant was born without complicationsby normal vaginal delivery.
Figure 1. Genotypic Analysis of the Kindred of the Proband with the Jervell and Lange-Nielsen Syndrome, Showing the Linkage between KVLQT1 and the Phenotype of the Long-QT Syndrome.
Circles indicate female family members, squares male family members, and slashes deceased family members. The left side of each symbol indicates whether the subject had the phenotype of the long-QT syndrome; the right side denotes the subject's hearing status. Black denotes affected status, gray uncertain status, and white unaffected status. The proband (Patient V-5) is indicated by the solid circle representing both the long-QT syndrome and deafness. The genotypes of the polymorphic markers TH and D11S1318 and the KVLQT1 mutation (282–283insG) are shown beneath each symbol, with inferred genotypes given in parentheses and hyphens indicating unknown alleles. For KVLQT1, the normal allele is designated by 1 and the mutant allele by 2. Genotypes associated with the long-QT syndrome are shown in boxes. The subjects' QTc intervals are given immediately below the genotypes, with their ages (in years) below the QTc intervals. NA denotes not available. The KVLQT1 mutant allele cosegregates with the phenotype of the long-QT syndrome in this family, and the proband with the Jervell and Lange-Nielsen syndrome is homozygous for the mutation.
The slow heart rate persisted after birth. One hour after delivery,at the time of the first bottle feeding, the infant had cyanosisand hypotonia. She was rushed to the pediatric intensive careunit. Her serum electrolytes and a hematologic evaluation werenormal. Blood cultures, urinalysis, urine cultures, and a chestfilm were negative. An electrocardiogram showed sinus bradycardiawith a rate of 82 beats per minute and prolongation of the QTinterval, with a QTc of 0.61 sec1/2. On the third hospital day,a pediatric cardiologist made the diagnosis of the long-QT syndromeand treatment with propranolol was started. On the eighth day,audiograms indicated bilateral sensory deafness. A neurologicevaluation was otherwise unremarkable, and no evidence of brain-stemdysfunction was found. There was no evidence of dysmorphology.
On day 10, the infant was sent home with an apnea monitor. Atthe age of four weeks, serial audiograms revealed no responsesto auditory stimuli in a soundproof room or through earphones.Trials with battery-powered behind-the-ear hearing aids alsoindicated no responses. There was no evidence of infection,meningitis, or temporal bone fractures and no history of treatmentwith ototoxic drugs. At 26 months the proband continued to betreated with propranolol and had no documented syncope, seizures,or tachyarrhythmia.
The family members were not evaluated further. Seven monthsafter the delivery of the proband, her mother had a cardiacarrest and died when her alarm clock sounded. She was exhaustedand extremely anxious at the time.
After the mother's death, the family was referred to our laboratoryfor genetic evaluation. Phenotypic analysis revealed that 14family members had prolonged QTc intervals ranging from 0.47to 0.53 sec1/2 (Figure 1). Thirty-two family members had borderlineQTc intervals, ranging from 0.42 to 0.46 sec1/2 . Six familymembers reported a history of syncope. Three had had one syncopalepisode each: Subject II-13 (QTc, 0.46 sec1/2 ; precipitatingcause of syncope unknown), Subject III-29 (QTc, 0.49 sec1/2; syncope while smoking marijuana), and Subject IV-4 (QTc, 0.51sec1/2 ; syncope while exercising). Three other family membershad multiple episodes of syncope: Subject III-27 (QTc, 0.53sec1/2 ; syncope while exercising), Subject III-33 (QTc, 0.46sec1/2 ; precipitating cause of syncope unknown), and SubjectIV-14 (QTc, 0.41 sec1/2 ; syncope while exercising or at rest).None of the family members reported hearing deficits. Formalaudiometric analyses of Subjects IV-4, V-1, and V-3 showed normalhearing.
On the basis of this inspection, it is apparent that the phenotypeof the long-QT syndrome is inherited as an autosomal dominanttrait in this kindred (Figure 1). This pattern of inheritanceis characterized by transmission of the disease phenotype fromparent to child, the presence of the phenotype in each generation,and the involvement of both sexes. Father-to-son transmissionis observed in this family, a fact that rules out X-linked inheritance.
Linkage Analysis
We used linkage analysis to determine whether the gene responsiblefor the long-QT syndrome in this kindred was located on thesame chromosome as one of the known autosomal dominant genesfor the long-QT syndrome. The polymorphic markers TH and D11S1318,which map to the KVLQT1 region of chromosome 11, were completelylinked to the long-QT syndrome phenotype.17 The lod scores forlinkage were 4.70 and 5.46 at a recombination fraction of 0.00for TH and D11S1318, respectively (P<0.001 for both markers)(Table 1). These data indicate that KVLQT1 is an excellent candidatefor the gene that causes the long-QT syndrome in this family.
Table 1. Pairwise Lod Scores for the Kindred Studied, Relating the Phenotype of the Long-QT Syndrome to Markers at Chromosome 11p15.5, Including the KVLQT1 Mutation.
Mutation Analysis
We screened DNA samples from affected subjects for functionalmutations in KVLQT1, using SSCP to detect mutations. An abnormalband was observed in affected members of the family, but notunaffected ones (Figure 1 and Figure 2). The proband with theJervell and Lange-Nielsen syndrome (Patient V-5) had two copiesof the abnormal SSCP band. Linkage analysis indicated that theabnormal band was completely linked to the long-QT syndromephenotype in this family, with a lod score of 5.08 at a recombinationfraction of 0.00 (Table 1). This indicates odds of more than100,000 to 1 in favor of linkage and corresponds to P<0.001.The abnormal SSCP band was not observed in DNA samples from200 unrelated control subjects (a total of 400 chromosomes).
Figure 2. Cosegregation of the Abnormal SSCP Band with the Phenotype of the Long-QT Syndrome in the Kindred of the Proband with the Jervell and Lange-Nielsen Syndrome, with the DNA Sequence of the KVLQT1 Mutation.
The top panel shows a subgroup of the kindred. The symbols are as described in the legend and key to Figure 1. Small symbols denote family members for whom no bands are shown but who are included to clarify the family relationships. The abnormal SSCP band cosegregates with the phenotype of the long-QT syndrome. The bottom panel shows the DNA and protein sequences of the normal and mutant KVLQT1 alleles. The mutant allele contains an insertion of a single nucleotide (G) after nucleotide 282. This insertion causes a frame shift that leads to a premature stop codon.
DNA-sequence analysis revealed that the abnormal SSCP band containedthe insertion of a single nucleotide (G) after nucleotide 282of the KVLQT1 sequence (numbering started at the A nucleotidein the ATG initiation codon; GenBank accession number U89364).This insertion causes a frame shift, disrupting the coding sequenceafter the second putative membrane-spanning domain of the KVLQT1protein and leading to a premature stop codon at nucleotide564.
We next assessed the range of QTc intervals in this genotypicallydefined population. For the proband, who had a homozygous mutationof KVLQT1, the mean (±SD) QTc as calculated on the basisof eight electrocardiograms was 0.54±0.05 sec1/2. Bycontrast, the mean QTc in 24 persons with one mutant KVLQT1allele (who were tested with one electrocardiogram each) was0.47±0.04 sec1/2 . In the 28 family members with no KVLQT1mutations, the mean QTc was 0.43±0.02 sec1/2 . Althoughno formal statistical analysis could be performed because therewas only one homozygote in the family, the QTc interval of theproband (0.54 sec1/2 ) was markedly higher than the mean valuein the heterozygotes (0.47 sec1/2). This suggests that patientswith two copies of a mutant KVLQT1 gene may have longer QTcintervals than those with a single mutant copy.
Discussion
We have described a family with an autosomal dominant long-QTsyndrome resulting from a mutation of KVLQT1. Family memberswith one mutant KVLQT1 allele had the long-QT syndrome but hadnormal hearing. One family member had the typical features ofthe Jervell and Lange-Nielsen syndrome: marked QTc prolongationand congenital sensory deafness.1,2,4 This person presentedwith bradycardia in utero. She was the offspring of a consanguineousmarriage and had two copies of the mutant KVLQT1 allele. Weconclude that homozygous mutation of KVLQT1 causes the Jervelland Lange-Nielsen syndrome.
Recent genetic and physiologic data support the conclusion thathomozygous KVLQT1 mutations cause deafness. We and others recentlydiscovered that KVLQT1 protein joins with minK protein to formcardiac IKs potassium channels.19,20 Although most studies havefocused on the function of minK in the heart, the gene thatencodes it is also expressed in the inner ear. MinK knockoutmice are deaf and have inner-ear disease similar to that ofpatients with the Jervell and Lange-Nielsen syndrome.25,26 Theloss of functional minK protein apparently disrupts the productionof endolymph, leading to deafness. Recently, Neyroud and colleaguesshowed that KVLQT1 is expressed in the stria vascularis of theinner ear in mice.27 Other known genes located near KVLQT1 (p57KIP2,H19, and the genes for insulin-like growth factor II, insulin,and tyrosine hydroxylase) are not likely to contribute to thedisease observed in the Jervell and Lange-Nielsen syndrome.These data are consistent with the finding that homozygous mutationsof KVLQT1 cause deafness in humans.
The KVLQT1 mutation described here causes a frame shift, disruptingthe coding sequence and leading to a premature stop codon. Theresulting truncated protein would lack a pore region and couldnot function as an ion channel. Thus, the proband representsa case of functional knockout of KVLQT1. The result is prolongedmyocellular repolarization, lack of homogeneity of cardiac repolarization,increased risk of torsade de pointes arrhythmias, and deafness.
It is not yet clear whether KVLQT1 is the only gene responsiblefor the Jervell and Lange-Nielsen syndrome. Genetic heterogeneityhas been identified in the autosomal dominant long-QT syndrome(Table 2),15,16,17 and Jeffrey and colleagues described a familywith the Jervell and Lange-Nielsen syndrome in which the phenotypewas not linked to a chromosome 11p15.5 marker.28 In findingsconsistent with ours, Neyroud and colleagues recently reportedhomozygous KVLQT1 mutations associated with the Jervell andLange-Nielsen syndrome in two kindreds.27 Because minK joinswith KVLQT1 protein to form IKs channels, minK is another excellentcandidate gene for this disorder.19,20
Table 2. Molecular Genetics of the Long-QT Syndrome.
Previous reports describing the clinical characteristics ofpatients with the Jervell and Lange-Nielsen syndrome have focusedon the dramatic features observed, which generally include markedprolongation of the QTc interval, frequent tachyarrhythmias,and deafness. Some studies have documented moderate prolongationof QTc in family members with normal hearing, but the Romano–Wardlong-QT syndrome was not diagnosed.2,3 The family describedin our study came to our attention because the proband's motherdied suddenly, presumably of a cardiac arrhythmia. Phenotypicevaluation of the extended family revealed autosomal dominantinheritance of the long-QT syndrome in other family members.Deafness, however, was found only in the proband, who was homozygousfor the KVLQT1 mutation. Thus, one feature of the phenotypeof the Jervell and Lange-Nielsen syndrome, deafness, is inheritedas an autosomal recessive trait. QTc prolongation, by contrast,is inherited as a dominant trait, but that phenotype may bemore severe if both alleles are mutant. It is important to notethat the parents (and possibly other family members) of patientswith the Jervell and Lange-Nielsen syndrome are obligate heterozygotesfor long-QT–associated mutations and are at increasedrisk for arrhythmia. The untimely death of the proband's motherpoints to the importance of electrocardiographic and geneticscreening of families with the Jervell and Lange-Nielsen syndrome.
Supported by a grant (RO1 HL48074) from the National Heart,Lung, and Blood Institute, by a Specialized Center of ResearchGrant (HL53773), by a grant (M01 RR00064) from the Public HealthService, by the Technology Access Section of the Utah GenomeCenter, by the American Heart Association, and by an award fromBristol-Myers Squibb.
We are indebted to the family members for their participation;to Dr. S. Appleton for referring the family; to M. Sanguinetti,L. Urness, and S. Odelberg for critical review of the manuscript;to S. Wilson for blood collection; and to the Sudden ArrhythmiaDeath Syndrome Foundation.
Source Information
From the Eccles Institute of Human Genetics (I.S., D.L.A., M.T.K.), the Cardiology Division (K.W.T., G.M.V., M.T.K.), and the Howard Hughes Medical Institute (D.L.A., M.T.K.), University of Utah; and the Department of Medicine (K.W.T., G.M.V.), Latter-Day Saints Hospital — all in Salt Lake City.
Address reprint requests to Dr. Keating at the Howard Hughes Medical Institute, Suite 5100 EIHG, University of Utah, Salt Lake City, UT 84112.
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