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The long-QT syndrome
BRIEF REVIEWS The Long-QT Syndrome Genetic Considerations Arthur J. Moss and Jennifer L. Robinson
The familial long-QT syndrome (LQTS) is an infrequently occuwing disorder in which affected family members have QTprolongation on the ECG, often associated with recurrent syncope and fatal ventricular arrhythmias. Autosomal recessive and autosomal dominant modes of inheritance were suggested by the pattern of occurrence of this disorder in the first reported LQTS f amilies. Statistical genetic analysis (segregation analysis) has substantiated a major gene effect on QTc length in two large pedigrees. Gene linkage studies have uncovered tight linkage between a DNA marker at the Harvey ras-I locus on chromosome II and LQTS in one large pedigree, substantiating a genetic basis of this disorder. (Trends Cardiovasc Med 1992;2:81-83)
l
Historical Background
The first family with long-QT syndrome (LQTS) was described by Jervell and Lange-Nielsen (1957). In this family, three of four deaf children (one boy and three girls) died suddenly. The deaf children had many fainting attacks precipitated by acute arousal emotions and exercise, and the QT interval was markedly prolonged in three of them; one of the deceased never had an electrocardiogram (ECG). The three deaths occurred at the age of 4, 5, and 9 years while the children were playing. Two other children and the parents were healthy, with normal hearing and normal ECGs. I-XXine and Woodworth (1958) reported a similar case-a 13-year-old deaf boy with QT prolongation and recurrent syncope who died suddenly; both parents were normal and there was no consanguinity. This combination of congenital deafness, QT prolongation, and Arthur J. Moss and Jennifer L. Robinson are at the Department of Medicine and the Heart Research Follow-up Program of the Department of Community and Preventive Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
TCM Vol. 2, No. 3, 1992
recurrent syncope in five children from two sibships (four sudden deaths) and normal parents was interpreted as an autosomal recessive inheritance. This recessive pattern of inheritance was confirmed by Fraser et al. (1964) with their report of nine cases (three boys and six girls) in six sibships with the cardioauditory syndrome described by Jervell and Lange-Nielsen. Fraser noted that those heterozygous for the gene showed some moderate prolongation of the QT interval. They believed that the cardiac and auditory manifestations were pleiotropic expressions of the same gene defect. Hashiba (1978) reported seven additional cases (two boys and five girls) with the Jervell and Lange-Nielsen syndrome in which autosomal recessive inheritance provided the best interpretation of the data. It is interesting that among the first 21 reported cases, there was a 2: 1 ratio of females to males. Subsequent reports identified LQTS families with QT prolongation, syncope, and sudden death with normal hearing. Roman0 et al. (1963) and Ward (1964) reported individual families with QT prolongation in one of the parents and several affected children with recurrent syncope and sudden death. There was no
01992,
Elsevier Science Publishing Co., 1050-1738/92/$5.00
congenital deafness in these two families. Hashiba (1978) also reported an additional 28 families in Japan with this Romano-Ward syndrome. The 28 probands consisted of two males and 26 females, with nearly 100% penetrance of the phenotype from affected parents to off spring (120 affected among 189 examined family members). Segregation analysis supported an autosomal dominant inheritance. Presently, ~300 families have been reported in the world literature that fit the categorization of the RomanoWard syndrome (Schwartz et al. 1975; Moss et al. 199 1).
l
Clinical
Considerations
In 1979, our research group initiated a prospective study of proband-identified LQTS families including first- and seconddegree relatives to determine the hereditary aspects of LQTS. Moss et al. (1985) provided a preliminary report of the first 196 patients with LQTS enrolled in this program. Subsequently, Moss et al. (1991) reported the clinical characteristics and long-term course of 3343 individuals from 328 families in which one or more members were identified with LQTS (QTc > 0.44 s112). The enrolled patient population consisted of 328 probands and 3015 family members (688 with QTc > 0.44 s112 [affected], 1004 with QTc < 0.44 s112 [unaffected], and 1323 individuals without a recorded ECG [undetermined]). The first member of a family to be identified with LQTS, the proband, was usually brought to medical attention because of a syncopal episode during childhood or teenage years. Seven percent of the probands had congenital deafness. Probands (n = 328) were younger at first contact (21 + 15 [SD] years), more likely to be female (69%), and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%), congenital deafness (7%), a resting heart rate of <60/min (31%), QTc 2 0.50 s’j2 (52%), and a history of repetitive ventricular arrhythmias (47%) than other affected (n = 688) and unaffected (n = 1044) family members. Arrhythmogenic syncope often oc-
81
cm-red in association with acute physical, emotional, or auditory arousal. Not infrequently, the syncopal episodes were misinterpreted as a seizure disorder. By age 12,50% of the probands had experienced at least one syncopal episode or death. The rates of postenrollment syncope (one or more episodes) and LQTSrelated death before age 50 for probands (rz = 235; average follow-up 54 months per patient) were 5.0% per year and 0.9% per year, respectively; these event rates were considerably higher than those among affected and unaffected family members. The prospective long-term follow-up study of LQTS indicated that this disorder was largely familial in that 85% of probands had one or more family members with QTc > 0.44 s112.Some families were too small to evaluate the inheritance pattern properly. Our best estimate at this time is that -7% of affected probands represent the sporadic form of the disorder. The study population was nearly equally divided between those with QTc > 0.44 sm (n = 1016) and those with QTc IO.44 s112(rz = 1004). There was a variable severity of expression among those with QTc > 0.44 s112,suggesting that genetic factors other than simply the length of the QT interval affect the manifestations of this disease process. As in earlier reported studies, females predominated among the probands (69%) and affected family members (60%). Phenotypic Considerations
l
The phenotype for LQTS is an abnormally prolonged QT interval. The QT interval represents the time required from the onset of depolarization to the completion of the repolarization process in the axis of the lead chosen for measurement. Precise quantification of the QT interval is confounded by the imprecision in accurately identifying the end of the T wave on the scalar ECG. Under normal physiologic conditions, the QT interval shortens as the heart rate increases. The relationship between QT and cycle length (RR) has been described by a number of different regression formulae. The traditional criterion for the diagnosis of QT prolongation is a heart-rate-corrected QT interval (QTc) >0.44 s1j2, with QTc = QT/m. However, our recent studies on a large nor82
Table 1. The heart-rate-corrected QT interval (QTc): suggested values for diagnosing the long-QT syndrome QTc vokm9 l-15 Ymrs Normal Borderline Prolonged (top 1%)
<0.44 0.44-0.46 >0.46
by
age group8and gender Men Women co.43 0.43-0.45 >0.45
<0.45 0.45-0.46 >0.46
a The OTCvalues in the table are the measured QT interval in seconds divided by the square root of the RR cycle length in seconds. The normal QTc values are in s’~ and are derived from a population of 578 healthy subjects (Gottlieb et al. 1991).
ma1 population (Gottlieb et al. 1991) indicate that the QT interval is influenced by gender and age as well as heart rate, and these factors should be considered when diagnosing QT prolongation. Our own suggested categorization of QTc is to use a three-level classification (normal, borderline prolonged, and prolonged) adjusted for age and gender (Table 1).
l
Statistical Genetic Considerations
The mode of inheritance of a genetic disorder can be determined by evaluating the expression of phenotype frequencies (QTc) in the members of one or more families with the disorder (LQTS). This type of evaluation, usually referred to as segregation analysis, involves identification of the actual proportions (segregation frequencies) of observed dichotomized phenotypes (QTc > 0.44 s112and QTc I 0.44 s112)in a particular population. As Morton (1982) points out, segregation frequencies depend on gene frequencies, chance, the way the data are collected, and other factors. Complex segregation analysis permits evaluation of pedigrees with sporadic cases and allows for both continuous (QTc length) and discrete (dichotomized) traits in the hypothesized genetic models. Dr. Jean MacCluer (San Antonio, TX) has performed preliminary complex segregation analyses of QTc in 113 pedigrees without congenital deafness from our prospective LQTS study involving 2094 individuals, 1067 with QTc information. In the analysis of the total data set, the mode of QTc length inheritance was not clear-cut. In contrast, complex segregation analysis of QTc length in the largest pedigree, a 240-member Utah kindred ascertained through multiple probands, indicated that the best (most parsimonious) genetic model involved a
codominant major gene determining longQT intervals with a polygenic contribution also influencing QTc. Keating et al. (199 1) subsequently demonstrated that a gene determining LQTS is closely linked to the Harvey ra.s-1 locus on the short arm of chromosome 11 in this pedigree. Our recent analyses of a 164-member Iowa kindred provided further support for a major gene affecting QT interval length. We also have evidence of genetic heterogeneity, however, with a substantial polygenic component for QTc length in a 1OCmember Israeli pedigree. Our conclusion at this time is that LQTS is a heterogeneous disorder with an autosomal major gene affecting QTc length in some families, but other genes also appear to contribute to lengthened QTc. Whether different major genes are present in different families and whether the major genes have pleiotropic effects on clinical severity cannot be answered at this time.
l
GeneLinkage
Itoh et al. (1982) described a single Japanese family containing 10 members with the Romano-Ward syndrome and reported close linkage between the locus for QT prolongation and HLA loci on chromosome 6. We tried to verify these findings, and although our initial results in one Caucasian family were promising (Weitkamp and Moss 1985), more complete studies involving 14 kindreds did not provide statistically significant evidence for HLA-region genes contributing to QT prolongation in LQTS families (We& et al. 1989). Guifii-e et al. (1990) presented similar findings showing lack of HLA linkage in a molecular genetic study of six LQTS families. A major development in the genetic aspects of LQTS is the recent demonstration by Keating et al. (1991) that a
Q1992, Elsevier Science Publishing Co., 1050-1738/92/$5.00
TCM Vol. 2, No. 3, 1992
DNA marker at the Harvey rus- 1 locus on the short arm of chromosome 11 is tightly linked to LQTS in one large Utah pedigree without deafness. This linkage confirms for the first time a genetic basis of this disorder. The same Harvey uus-1 gene linkage has subsequently been found in six other small LQTS families, establishing some degree of genetic homogeneity, at least as far as the seven families are concerned. The tight linkage found by Keating is manifest by the lod score of 16.44 at zero recombination frequency. The lod score of 16.44 means that the odds in favor of Harvey rus- 1 linkage are 1 016.44 to 1. This finding indicates that the defective gene that causes LQTS is either in very close proximity to the Harvey r-us-1 gene or that the Harvey uas-1 gene itself is the actual LQTS gene. There are physiologic reasons for thinking that the Harvey ras-1 gene may be the candidate gene for LQTS. This gene encodes one of the membrane G proteins responsible for transmitting signals across the cell membrane and may regulate the flux of potassium ions through the cell membrane. Several investigators have hypothesized that the primary defect in LQTS is an alteration in myocellular membrane potassium conductance during phase 3 of the action potential (Schwartz et al. 1990). Regardless of whether or not the Harvey ras-1 gene is the defective gene in LQTS, the linkage will surely prove useful in the more precise diagnosis of this disorder. The finding by Keating et al. (199 1) provides an important first step toward ultimately understanding the genetic and molecular basis of repolarization-related cardiac arrhythmias.
l
Gottlieb S, Moss AJ, Hall WJ, et al.: 1991. Statistical identification of delayed repolarization: applicability in long QT syndrome (LQTS) population [abst]. J Am Coil Cardiol 17:241A. Giuffre RM, Hejtmancik JF, McCabe ERB, Towbin JA: 1990. Long QT (RomanoWard) syndrome: molecular genetic evidence against tight HLA linkage [abst]. Am J Hum Genet 47: 180A. Hashiba K: 1978. Hereditary QT prolongation syndrome in Japan: genetic analysis and pathological findings of the conducting system. Jpn Circ J 42:1133-l 150. Itoh S, Munemura S, Satoh H: 1982. A study of the inheritance pattern of the RomanoWard syndrome. Clin Pediatr 21:20-32. Jervell A, Lange-Nielsen F: 1957. Congenital deafmutism, functional heart disease with prolongation of the QT interval, and sudden death. Am Heart J 54:59-68. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M: 1991. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey YUS-1gene. Science 252:704706. Levine SA, Woodworth CR: 1958. Congenital deaf-mutism, prolonged Q-T interval, syncopal attacks and sudden death. N Engl J Med 259:412-417. Morton NE. ed: 1982. Outline of Genetic Epidemiology, 1982. New York, Karger, p 47.
Moss AJ, Schwartz PJ, Crampton RS, et al.: 1991. The long QT syndrome: prospective longitudinal study of 328 families. Circulation 841136-l 144. Roman0 C, Gemme G, Pongiglione R: 1963. Aritmie cardiache rare dell’eta pediatria. Clin Pediatr 451656-683. Schwartz PJ, Periti M, Malliani A: 1975. The long QT syndrome. Am Heart J 89:378390. Schwartz PJ, Iocati E, Priori SG, Zaza A: 1990. The idiopathic long QT syndrome. In Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia, WI3 Saunders, pp 589-605. Ward OC: 1964. New familial cardiac syndrome in children. J Irish Med Assoc 54:103-106. Weitkamp LR, Moss AJ: 1985. The long QT (Romanc+Ward) syndrome locus, LQT, is probably linked to HLA loci [abst]. Cytogenet Cell Genet 40:775. Weitkamp LR, Moss AJ, Schwartz PJ, et al.: 1989. Analysis of HLA haplotypes in long QT syndrome [abst]. In Proceedings of the Tenth International Workshop on Human Gene Mapping. New Haven, CT, 11-17 TCM June.
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Acknowledgments
This work was supported by grant HL33843 from the National Institutes of Health. The authors thank Mrs. Nancy Kellogg for her secretarial proficiency.
References Bazett HC: 1920. An analysis of the time relations of electrocardiogram. Heart 7:353367.
Use the business reply cards in this issue to order your personal subscription today--or call Else&r
Fraser GR, Fmggatt P, James TN: 1964. Congenital deafness associated with electrocardiogmphic abnormalities, fainting and sudden deaths. Q J Med 33:361-385.
TCM Vol. 2, No. 3, I992
Moss AJ, Schwartz PJ, Crampton RS, Locati E. Carleen E: 1985. The long QT syndrome: a prospective international study. Circulation 71:17-21.
Customer Service at:
(212) 633-3950 or FAX (212) 633-3880. 01992,
ElsevierScience Publishing
Co., 1050-1738/92/$5.00
83
The familial long-QT syndrome (LQTS) is an infrequently occuwing disorder in which affected family members have QTprolongation on the ECG, often associated with recurrent syncope and fatal ventricular arrhythmias. Autosomal recessive and autosomal dominant modes of inheritance were suggested by the pattern of occurrence of this disorder in the first reported LQTS f amilies. Statistical genetic analysis (segregation analysis) has substantiated a major gene effect on QTc length in two large pedigrees. Gene linkage studies have uncovered tight linkage between a DNA marker at the Harvey ras-I locus on chromosome II and LQTS in one large pedigree, substantiating a genetic basis of this disorder. (Trends Cardiovasc Med 1992;2:81-83)
l
Historical Background
The first family with long-QT syndrome (LQTS) was described by Jervell and Lange-Nielsen (1957). In this family, three of four deaf children (one boy and three girls) died suddenly. The deaf children had many fainting attacks precipitated by acute arousal emotions and exercise, and the QT interval was markedly prolonged in three of them; one of the deceased never had an electrocardiogram (ECG). The three deaths occurred at the age of 4, 5, and 9 years while the children were playing. Two other children and the parents were healthy, with normal hearing and normal ECGs. I-XXine and Woodworth (1958) reported a similar case-a 13-year-old deaf boy with QT prolongation and recurrent syncope who died suddenly; both parents were normal and there was no consanguinity. This combination of congenital deafness, QT prolongation, and Arthur J. Moss and Jennifer L. Robinson are at the Department of Medicine and the Heart Research Follow-up Program of the Department of Community and Preventive Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
TCM Vol. 2, No. 3, 1992
recurrent syncope in five children from two sibships (four sudden deaths) and normal parents was interpreted as an autosomal recessive inheritance. This recessive pattern of inheritance was confirmed by Fraser et al. (1964) with their report of nine cases (three boys and six girls) in six sibships with the cardioauditory syndrome described by Jervell and Lange-Nielsen. Fraser noted that those heterozygous for the gene showed some moderate prolongation of the QT interval. They believed that the cardiac and auditory manifestations were pleiotropic expressions of the same gene defect. Hashiba (1978) reported seven additional cases (two boys and five girls) with the Jervell and Lange-Nielsen syndrome in which autosomal recessive inheritance provided the best interpretation of the data. It is interesting that among the first 21 reported cases, there was a 2: 1 ratio of females to males. Subsequent reports identified LQTS families with QT prolongation, syncope, and sudden death with normal hearing. Roman0 et al. (1963) and Ward (1964) reported individual families with QT prolongation in one of the parents and several affected children with recurrent syncope and sudden death. There was no
01992,
Elsevier Science Publishing Co., 1050-1738/92/$5.00
congenital deafness in these two families. Hashiba (1978) also reported an additional 28 families in Japan with this Romano-Ward syndrome. The 28 probands consisted of two males and 26 females, with nearly 100% penetrance of the phenotype from affected parents to off spring (120 affected among 189 examined family members). Segregation analysis supported an autosomal dominant inheritance. Presently, ~300 families have been reported in the world literature that fit the categorization of the RomanoWard syndrome (Schwartz et al. 1975; Moss et al. 199 1).
l
Clinical
Considerations
In 1979, our research group initiated a prospective study of proband-identified LQTS families including first- and seconddegree relatives to determine the hereditary aspects of LQTS. Moss et al. (1985) provided a preliminary report of the first 196 patients with LQTS enrolled in this program. Subsequently, Moss et al. (1991) reported the clinical characteristics and long-term course of 3343 individuals from 328 families in which one or more members were identified with LQTS (QTc > 0.44 s112). The enrolled patient population consisted of 328 probands and 3015 family members (688 with QTc > 0.44 s112 [affected], 1004 with QTc < 0.44 s112 [unaffected], and 1323 individuals without a recorded ECG [undetermined]). The first member of a family to be identified with LQTS, the proband, was usually brought to medical attention because of a syncopal episode during childhood or teenage years. Seven percent of the probands had congenital deafness. Probands (n = 328) were younger at first contact (21 + 15 [SD] years), more likely to be female (69%), and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%), congenital deafness (7%), a resting heart rate of <60/min (31%), QTc 2 0.50 s’j2 (52%), and a history of repetitive ventricular arrhythmias (47%) than other affected (n = 688) and unaffected (n = 1044) family members. Arrhythmogenic syncope often oc-
81
cm-red in association with acute physical, emotional, or auditory arousal. Not infrequently, the syncopal episodes were misinterpreted as a seizure disorder. By age 12,50% of the probands had experienced at least one syncopal episode or death. The rates of postenrollment syncope (one or more episodes) and LQTSrelated death before age 50 for probands (rz = 235; average follow-up 54 months per patient) were 5.0% per year and 0.9% per year, respectively; these event rates were considerably higher than those among affected and unaffected family members. The prospective long-term follow-up study of LQTS indicated that this disorder was largely familial in that 85% of probands had one or more family members with QTc > 0.44 s112.Some families were too small to evaluate the inheritance pattern properly. Our best estimate at this time is that -7% of affected probands represent the sporadic form of the disorder. The study population was nearly equally divided between those with QTc > 0.44 sm (n = 1016) and those with QTc IO.44 s112(rz = 1004). There was a variable severity of expression among those with QTc > 0.44 s112,suggesting that genetic factors other than simply the length of the QT interval affect the manifestations of this disease process. As in earlier reported studies, females predominated among the probands (69%) and affected family members (60%). Phenotypic Considerations
l
The phenotype for LQTS is an abnormally prolonged QT interval. The QT interval represents the time required from the onset of depolarization to the completion of the repolarization process in the axis of the lead chosen for measurement. Precise quantification of the QT interval is confounded by the imprecision in accurately identifying the end of the T wave on the scalar ECG. Under normal physiologic conditions, the QT interval shortens as the heart rate increases. The relationship between QT and cycle length (RR) has been described by a number of different regression formulae. The traditional criterion for the diagnosis of QT prolongation is a heart-rate-corrected QT interval (QTc) >0.44 s1j2, with QTc = QT/m. However, our recent studies on a large nor82
Table 1. The heart-rate-corrected QT interval (QTc): suggested values for diagnosing the long-QT syndrome QTc vokm9 l-15 Ymrs Normal Borderline Prolonged (top 1%)
<0.44 0.44-0.46 >0.46
by
age group8and gender Men Women co.43 0.43-0.45 >0.45
<0.45 0.45-0.46 >0.46
a The OTCvalues in the table are the measured QT interval in seconds divided by the square root of the RR cycle length in seconds. The normal QTc values are in s’~ and are derived from a population of 578 healthy subjects (Gottlieb et al. 1991).
ma1 population (Gottlieb et al. 1991) indicate that the QT interval is influenced by gender and age as well as heart rate, and these factors should be considered when diagnosing QT prolongation. Our own suggested categorization of QTc is to use a three-level classification (normal, borderline prolonged, and prolonged) adjusted for age and gender (Table 1).
l
Statistical Genetic Considerations
The mode of inheritance of a genetic disorder can be determined by evaluating the expression of phenotype frequencies (QTc) in the members of one or more families with the disorder (LQTS). This type of evaluation, usually referred to as segregation analysis, involves identification of the actual proportions (segregation frequencies) of observed dichotomized phenotypes (QTc > 0.44 s112and QTc I 0.44 s112)in a particular population. As Morton (1982) points out, segregation frequencies depend on gene frequencies, chance, the way the data are collected, and other factors. Complex segregation analysis permits evaluation of pedigrees with sporadic cases and allows for both continuous (QTc length) and discrete (dichotomized) traits in the hypothesized genetic models. Dr. Jean MacCluer (San Antonio, TX) has performed preliminary complex segregation analyses of QTc in 113 pedigrees without congenital deafness from our prospective LQTS study involving 2094 individuals, 1067 with QTc information. In the analysis of the total data set, the mode of QTc length inheritance was not clear-cut. In contrast, complex segregation analysis of QTc length in the largest pedigree, a 240-member Utah kindred ascertained through multiple probands, indicated that the best (most parsimonious) genetic model involved a
codominant major gene determining longQT intervals with a polygenic contribution also influencing QTc. Keating et al. (199 1) subsequently demonstrated that a gene determining LQTS is closely linked to the Harvey ra.s-1 locus on the short arm of chromosome 11 in this pedigree. Our recent analyses of a 164-member Iowa kindred provided further support for a major gene affecting QT interval length. We also have evidence of genetic heterogeneity, however, with a substantial polygenic component for QTc length in a 1OCmember Israeli pedigree. Our conclusion at this time is that LQTS is a heterogeneous disorder with an autosomal major gene affecting QTc length in some families, but other genes also appear to contribute to lengthened QTc. Whether different major genes are present in different families and whether the major genes have pleiotropic effects on clinical severity cannot be answered at this time.
l
GeneLinkage
Itoh et al. (1982) described a single Japanese family containing 10 members with the Romano-Ward syndrome and reported close linkage between the locus for QT prolongation and HLA loci on chromosome 6. We tried to verify these findings, and although our initial results in one Caucasian family were promising (Weitkamp and Moss 1985), more complete studies involving 14 kindreds did not provide statistically significant evidence for HLA-region genes contributing to QT prolongation in LQTS families (We& et al. 1989). Guifii-e et al. (1990) presented similar findings showing lack of HLA linkage in a molecular genetic study of six LQTS families. A major development in the genetic aspects of LQTS is the recent demonstration by Keating et al. (1991) that a
Q1992, Elsevier Science Publishing Co., 1050-1738/92/$5.00
TCM Vol. 2, No. 3, 1992
DNA marker at the Harvey rus- 1 locus on the short arm of chromosome 11 is tightly linked to LQTS in one large Utah pedigree without deafness. This linkage confirms for the first time a genetic basis of this disorder. The same Harvey uus-1 gene linkage has subsequently been found in six other small LQTS families, establishing some degree of genetic homogeneity, at least as far as the seven families are concerned. The tight linkage found by Keating is manifest by the lod score of 16.44 at zero recombination frequency. The lod score of 16.44 means that the odds in favor of Harvey rus- 1 linkage are 1 016.44 to 1. This finding indicates that the defective gene that causes LQTS is either in very close proximity to the Harvey r-us-1 gene or that the Harvey uas-1 gene itself is the actual LQTS gene. There are physiologic reasons for thinking that the Harvey ras-1 gene may be the candidate gene for LQTS. This gene encodes one of the membrane G proteins responsible for transmitting signals across the cell membrane and may regulate the flux of potassium ions through the cell membrane. Several investigators have hypothesized that the primary defect in LQTS is an alteration in myocellular membrane potassium conductance during phase 3 of the action potential (Schwartz et al. 1990). Regardless of whether or not the Harvey ras-1 gene is the defective gene in LQTS, the linkage will surely prove useful in the more precise diagnosis of this disorder. The finding by Keating et al. (199 1) provides an important first step toward ultimately understanding the genetic and molecular basis of repolarization-related cardiac arrhythmias.
l
Gottlieb S, Moss AJ, Hall WJ, et al.: 1991. Statistical identification of delayed repolarization: applicability in long QT syndrome (LQTS) population [abst]. J Am Coil Cardiol 17:241A. Giuffre RM, Hejtmancik JF, McCabe ERB, Towbin JA: 1990. Long QT (RomanoWard) syndrome: molecular genetic evidence against tight HLA linkage [abst]. Am J Hum Genet 47: 180A. Hashiba K: 1978. Hereditary QT prolongation syndrome in Japan: genetic analysis and pathological findings of the conducting system. Jpn Circ J 42:1133-l 150. Itoh S, Munemura S, Satoh H: 1982. A study of the inheritance pattern of the RomanoWard syndrome. Clin Pediatr 21:20-32. Jervell A, Lange-Nielsen F: 1957. Congenital deafmutism, functional heart disease with prolongation of the QT interval, and sudden death. Am Heart J 54:59-68. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M: 1991. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey YUS-1gene. Science 252:704706. Levine SA, Woodworth CR: 1958. Congenital deaf-mutism, prolonged Q-T interval, syncopal attacks and sudden death. N Engl J Med 259:412-417. Morton NE. ed: 1982. Outline of Genetic Epidemiology, 1982. New York, Karger, p 47.
Moss AJ, Schwartz PJ, Crampton RS, et al.: 1991. The long QT syndrome: prospective longitudinal study of 328 families. Circulation 841136-l 144. Roman0 C, Gemme G, Pongiglione R: 1963. Aritmie cardiache rare dell’eta pediatria. Clin Pediatr 451656-683. Schwartz PJ, Periti M, Malliani A: 1975. The long QT syndrome. Am Heart J 89:378390. Schwartz PJ, Iocati E, Priori SG, Zaza A: 1990. The idiopathic long QT syndrome. In Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia, WI3 Saunders, pp 589-605. Ward OC: 1964. New familial cardiac syndrome in children. J Irish Med Assoc 54:103-106. Weitkamp LR, Moss AJ: 1985. The long QT (Romanc+Ward) syndrome locus, LQT, is probably linked to HLA loci [abst]. Cytogenet Cell Genet 40:775. Weitkamp LR, Moss AJ, Schwartz PJ, et al.: 1989. Analysis of HLA haplotypes in long QT syndrome [abst]. In Proceedings of the Tenth International Workshop on Human Gene Mapping. New Haven, CT, 11-17 TCM June.
Why wait for it to circulate? Read your own copy of
.
MEDICINE
l
If you share TCM with others at work, you know what goes around doesn’t always come around. And if it does, articles are oRen dated or sometimes clipped. Why miss a single issue, or wait weeks to read one? By starting your personal subscription, for just $60 you’ll be guaranteed to read each and every issue. TRENDS IN CARDIOVAMXJLAR MEDICINE’s short reviews on ‘hot” topics can make a difference in your research and practice. Commissioned researchers and clinicians report on advances in cardiology and its related areas.
Acknowledgments
This work was supported by grant HL33843 from the National Institutes of Health. The authors thank Mrs. Nancy Kellogg for her secretarial proficiency.
References Bazett HC: 1920. An analysis of the time relations of electrocardiogram. Heart 7:353367.
Use the business reply cards in this issue to order your personal subscription today--or call Else&r
Fraser GR, Fmggatt P, James TN: 1964. Congenital deafness associated with electrocardiogmphic abnormalities, fainting and sudden deaths. Q J Med 33:361-385.
TCM Vol. 2, No. 3, I992
Moss AJ, Schwartz PJ, Crampton RS, Locati E. Carleen E: 1985. The long QT syndrome: a prospective international study. Circulation 71:17-21.
Customer Service at:
(212) 633-3950 or FAX (212) 633-3880. 01992,
ElsevierScience Publishing
Co., 1050-1738/92/$5.00
83