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(Circulation Research. 1995;77:735-740.)
© 1995 American Heart Association, Inc.

Articles

An Isolated Cardiac Conduction Disease Maps to Chromosome 19q

Anne de Meeus, Edouard Stephan, Sophie Debrus, Marie-Kamala Jean, Jacques Loiselet, Jean Weissenbach, Jacques Demaille, Patrice Bouvagnet

From CRBM, CNRS UPR 9008, and INSERM U249 (A. de M., S.D., M.-K.J., J.D., P.B.), Montpellier, France; Faculté de Médecine (E.S.) and Département de Biochimie (J.L.), Université Saint Joseph, Beyrouth, Lebanon; and Service de Génotypage, Généthon (J.W.), Evry, France.

Correspondence to Dr Patrice Bouvagnet, CRBM, CNRS, BP: 5051, 34033 Montpellier Cedex, France. E-mail coeur@crbm2.crbm.cnrs-mop.fr.

	Abstract

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Abstract Isolated cardiac conduction disease is an autosomal dominant defect that includes various combinations of bundle branch or fascicular blocks. These defects can cause sudden death due to a complete heart block. We used a genome-wide screening approach with polymorphic (CA)n repeat markers to determine the chromosomal position of the gene defect implicated in this disorder. The analyses were carried out on a large Lebanese kindred, which included individuals with either a complete or incomplete right bundle branch block (RBBB) with a vertical-axis deviation (-30 or +100). Linkage to the disease locus was detected with the polymorphic marker D19S604 on the q arm of chromosome 19 (19q13.3) with a multipoint lod score of 7.18. Additionally, we were able to exclude the flanking loci D19S606 and D19S571, which are 13 cM apart because of recombination events in three affected individuals. The histidine-rich calcium-binding protein gene is found in this region and is an attractive candidate gene on the basis of its physiological properties and a tight linkage. There is no expansion in two exon 1 regions known for a variable number of triplet repeats.

Key Words: conduction block • familial disorders • chromosome 19 • sudden death

	Introduction

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Familial disorders of the cardiac conduction system are a serious health problem, because they may cause perinatal, infantile, and adult sudden death probably due to complete heart block.^{1 2 3 4 5 6 7 8 9} The most frequent conduction disorder is RBBB. This block can be isolated or associated with other cardiac blocks, such as atrioventricular block, a left anterior or posterior hemiblock, or some other minor abnormalities.^{7 8 9 10 11 12 13 14 15 16 17 18} Additionally, these blocks can be associated with a rhythm disturbance.³ The onset of these conduction disorders can vary from birth to adulthood and may be progressive.^{6 7 9 12 13 19} In some of these cases, the disease is transmitted as an autosomal dominant mendelian trait^{2 3 4 5 6 7 8 11 12 13 15 20} and is referred to as such in Mendelian Inheritance of Man.²¹ Therefore, a family survey of cardiac conduction cases is of great value and may give us better insight into the natural history and relative distribution of conduction system diseases in the general population. In fact, the actual proportion of familial cases is not known, although there have been some reports demonstrating an increased incidence of conduction disorders in families with individuals affected with a unifascicular or bifascicular block.^{22 23} To date, there have been no candidate genes implicated in isolated conduction disorders. However, three genetic linkage studies of familial conduction disorder have been reported recently.^{24 25 26} The first study dealt with a gene defect that causes conduction blocks associated later in life with dilated cardiomyopathy, and the gene was mapped to chromosome 1p1-q1.²⁴ The second study concerned a progressive familial heart block in six pedigrees and excluded 35% of the genome by using 80 polymorphic markers.²⁵ The last study has recently identified an X-linked gene, STA, responsible for Emery-Dreifuss muscular dystrophy, a muscular disease and cardiomyopathy that is manifested as a cardiac conduction defect.²⁶

Since no obvious candidate genes nor cytogenetic abnormalities pointed at putative chromosomal regions at the time we started the present study, we carried out a genome-wide approach with polymorphic markers in a large Lebanese kindred first described by Stephan^{7 8} in 1978 as family Z. Markers used for the genome-wide approach on 79 family members are polymorphic (CA)n repeats from Généthon.²⁷ We report here a significant linkage of the mutation to a group of markers on chromosome 19q and suggest that HRC²⁸ is an attractive candidate gene in this family for ICCD.

	Materials and Methods

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Clinical Evaluation
Informed consent was obtained from participants (or from parents of minors) before blood was drawn. ECG and echocardiograms were interpreted according to standard criteria.^{29 30 31}

Genotyping
Blood (20 mL) was obtained from 79 individuals of the Lebanese kindred. Forty-one EBV-transformed B-cell lines were established, and DNA was extracted by using standard procedures. Most PCR reactions were performed at the Généthon center as described by Vignal.³² Généthon, HRC intron B,³³ and CHLC³⁴ markers were processed with PCR conditions identical to those described elsewhere.³² Genotypes were ascertained without knowledge of their clinical status.

Linkage Analysis
Two-point lod scores and multipoint analyses were carried out with the programs MLINK, LODSCORE, and LINKMAP of the LINKAGE package (FASTLINK, version 2.20).³⁵ A mutation frequency of 1:1000 was assumed on the basis of a previous report by Hiss and Lamb.¹⁰ Individuals whose phenotype status was doubtful (indeterminate; see "Clinical Evaluation") were not scored for penetrance estimation. The analysis of the disease status of 114 offspring of affected parents in our kindred resulted in a penetrance value of 70% for males and 30% for females. Linkage analyses were carried out by using these as well as other penetrance values (see "Results"). Allele frequencies were those provided by Gyapay et al²⁷ , authors' unpublished data (1994), and Hofmann et al.³³ The allele distributions of polymorphic loci in the Lebanese population are very similar to those of Caucasians.³⁶ No sex difference in recombination fraction was assumed. The disease status of indeterminate patients as described in "Results" was set to 0.

	Results

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Clinical Evaluations
The Lebanese kindred descends from a single polygamous ancestor who died presumably of complete heart block and who engendered >400 descendants in five generations. As of March 1993, there were 337 members in this kindred, of which 52 were found to be affected with conduction disorders. As part of this study, 79 participants (more than four generations) were reevaluated by history, physical exam, and serial 12-lead ECG (Fig 1). In addition, nine individuals with a conduction block agreed to have a two-dimensional echocardiogram. Twenty individuals were diagnosed by ECG studies as having either a complete RBBB with or without a QRS frontal-axis deviation or an incomplete RBBB with a QRS frontal-axis deviation (-30 or +100) (Table 1). Incomplete and complete RBBBs were diagnosed according to standard criteria.^{29 30} The ECG of patient IV-5 (Fig 1) is presented as an example in Fig 2. Additionally, the affection status of 12 individuals could not be ascertained with certainty, because they had either (1) an incomplete RBBB with a normal frontal QRS axis or minor ECG anomalies (6 individuals) or (2) a normal ECG at the time of the study but a previous ECG showing incomplete RBBB or minor anomalies (6 individuals). One of these 12 individuals did not give blood (III-6). Because these anomalies are minor or intermittent, we scored these individuals with an affection status of "indeterminate." Of the 79 participants, no one complained of shortness of breath or episodes of faintness. With no exception, none had chronic pulmonary or cardiovascular disease. Individual III-2 had hypertension and non–insulin-dependent diabetes and was on cardiovascular medicine. All two-dimensional echocardiograms were normal, with no evidence of either hypertrophied or dilated cardiomyopathy.³¹

View larger version (32K): [in this window] [in a new window]   Figure 1. A Lebanese family genetic map showing inheritance of an ICCD. Generations are indicated on the left side. For the sake of clarity, only the 79 participants in the present study and their ancestors are represented on this pedigree tree. Haplotypes are indicated below each individual, with paternal alleles on the left and maternal alleles on the right when possibly inferred. For individuals with parents that are not typed, the side is arbitrarily chosen. Haplotypes were constructed in order to minimize recombination events, which are symbolized by an "x." Some recombinations may be undetected because of homozygous parental genotypes. The haplotype inherited from the common ancestor (I-2) is boxed. From top to bottom (centromere to telomere), numbers are as follows: D19S606, D19S604, HRC intron B, and D19S571. The position of HRC intron B relative to D19S604 is arbitrary, since no recombinations were observed in this pedigree. Affection status is shown as follows: solid symbol, affected; clear symbol, unaffected; and stippled symbol, uncertain clinical status.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Affected Individuals in Family Z

View larger version (60K): [in this window] [in a new window]   Figure 2. ECG of patient IV-5 (Fig 1). He has a vertical QRS-axis deviation and a complete RBBB with an rR' pattern. The QRS duration is superior to 0.12 second. Note the large S wave in D1, aVL, and V3 to V6.

Linkage Analysis
A subset (165) of the 2066 Généthon markers²⁷ was selected for a linkage study on a subgroup of 24 (17 affected or carrier, 6 unaffected, and 1 control) individuals. The 165 markers were selected according to their high heterozygosity and average intermarket genetic distance of 20 to 30 cM. Clues that the disease gene might be located on chromosome 19q came from two adjacent markers (D19S219 and D19S210), which gave positive lod scores. To confirm linkage of the defect to this region, these markers and six additional AFM (CA)n repeats that mapped between D19S219 and D19S210 were analyzed for all participants. Five of these six additional markers are newly identified microsatellites, whereas one (D19S418) has been published previously.²⁷ Table 2 presents the locus name and primer sequences for the newly characterized loci. The assignment of these markers to 19q and the genetic map of this chromosomal region was determined on CEPH (Centre dEtudes pour le Polymorphisme Humain) families (J. Weissenbach, unpublished data, 1994) (Fig 3). The pairwise lod scores obtained between the mutation and each of these six markers are shown in Table 3. A maximum lod score of 6.31 at =0.00 was achieved with marker D19S604.

View this table: [in this window] [in a new window]   Table 2. Five New Généthon Markers and Their Primer Sequences

View larger version (17K): [in this window] [in a new window]   Figure 3. Genetic map of a segment of 19q between locus D19S219 and D19S210 showing the location of the disease locus in this family. The order of loci and map distances between markers are based on unpublished Généthon data (J. Weissenbach). Asterisks indicate newly identified microsatellite loci. The approximate location of the region on chromosome 19 is shown on the left side.

View this table: [in this window] [in a new window]   Table 3. Pairwise Lod Scores Between Chromosome 19q Markers and the Disease Locus, With Penetrance Values of 30% for Females and 70% for Males

To map this mutation precisely, a multipoint linkage analysis was carried out on this set of markers. A maximum multipoint lod score of 7.18 was reached at locus D19S604, with a confidence interval (1–lod-unit decrease in likelihood) of 3 cM toward the centromere and 7 cM toward the telomere, giving odds of 14 000 000:1 that the mutation is mapped next to this locus (Fig 4). Furthermore, analysis of haplotypes in this large family identified no recombinations between this marker and the disease gene (Fig 1). On the basis of these results, we would conclude that the disease locus is very closely linked to D19S604. Moreover, because of a recombination event in individuals IV-1, IV-5, and V-6, the flanking loci D19S606 and D19S571 could be excluded (Figs 1 and 3). These markers are 4 cM centromeric and 9 cM telomeric to D19S604, respectively.

View larger version (16K): [in this window] [in a new window]   Figure 4. Multipoint linkage analysis of ICCD in the D19S606 (centromeric) to D19S605 (telomeric) interval, with penetrance values of 30% for females and 70% for males. The y axis represents the multipoint lod score (log10 value); the x axis represents the genetic distance along this interval. The zero location denotes the most centromeric marker of this interval (D19S606). The multipoint analysis was repeated for one liability class and penetrance values of 30%, 50%, 70%, and 90%. These values had a small effect on the maximum lod score, which was always >5, and no effect on the peak location score.

Candidate Gene
Distal markers of the CHLC framework map of chromosome 19 as well as a polymorphic marker located within intron B of the HRC^{33 37} were typed in this Lebanese family. HRC is expressed in cardiac tissue.³⁷ This locus was tightly linked to marker D19S604 (maximum lod score, 17.8 at =0.00), the locus linked to the disease gene. Two-point analysis between the affection status and HRC intron B demonstrated tight linkage, with a lod score of 3.02 (=0.00). Furthermore, the haplotype analysis did not reveal a single recombination between these loci. Because HRC has been mapped to the 19q13.3 band,³³ the ICCD disease gene is presumably mapped to the same location. Analysis of two variant trinucleotide repeats, (GAT)n and (GAG)n in exon 1,³³ did not reveal any increased length in affected individuals. If HRC was the ICCD locus, an expansion of these trinucleotide repeats as a factor in disease induction has been eliminated.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
ICCD is different from the conduction disease described by Graber et al³⁸ in that patients in their study evolved toward severe cardiomyopathy with congestive heart failure and ventricular arrhythmias. In ICCD, however, there is no sign of direct myocardial involvement even among the oldest individuals. Moreover, Graber et al mapped the conduction disease with cardiomyopathy to 1p1-1q1, whereas ICCD maps to chromosome 19q.

In the present study, we report a penetrance of ICCD in our kindred that is lower than that in the study of PFHB1 by Brink et al.²⁵ Nevertheless, in the present study, the multipoint analysis gave lod score values above the threshold of 3 within a large range of penetrances. Moreover, there was no variation in the peak location, which was in any case centered on marker D19S604 and HRC intron B.

For those individuals with labile minor anomalies, it is impossible to know a priori whether or not they carry the mutation (phenocopies). This is why they were pooled in an indeterminate group. Misclassifying noncarriers in the affected group would seriously impede the linkage study, whereas misclassifying carriers in the unaffected group would moderately decrease the power of the analysis. It introduces a bias in the penetrance evaluation, but we showed that analysis of this large family with highly polymorphic markers is robust to varying values of penetrance. A retrospective look at these minor anomalies in light of their evolutionary course and the genotypes may allow the identification of specific signs discriminating between phenocopies and early ICCD.

Stephan^{2 8} and Brink and Torrington⁶ reported a number of sudden deaths in these families, with a peak in neonates, infants, and late adults. Brink and Torrington⁶ also suggested an increased risk near adolescence. Although stable for long periods, these conduction blocks may more or less abruptly lead to complete atrioventricular blocks. It is important to evaluate whether carriers of the mutation with normal ECG are prone to develop conduction defects during life.

Genetic mapping of the disease locus showed a very close linkage between the disease gene and the HRC gene. HRC is a protein of 165 kD that is located in the lumen of the sarcoplasmic reticulum. It binds to Ca²⁺ on nitrocellulose blots, but its role in Ca²⁺ homeostasis remains to be determined. The tissue-specific expression of this protein is limited to skeletal and heart muscle³⁷ as well as arteriolar smooth muscle cells in the rabbit.²⁸ Although members of this family and other reported families with ICCD do not suffer from overt skeletal or vascular dysfunction, HRC may be considered an attractive candidate gene for cardiac conduction disease because of its expression in cardiac tissue and tight linkage.

While the present report was under review, PFHB1 was mapped to 19q13.³⁹ The authors localized the mutation to an interval between the myotonic dystrophy locus and the telomere. The only polymorphic marker tested in this large region was localized within the KLK1 locus and gave a highly significant lod score (=0.00). The genetic interval where ICCD has been mapped (D19S606 to D19S571) lies in this large region, but it is not clear at this point whether ICCD and PFHB1 map to the same locus. According to CHLC maps, HRC lies 5.8 cM centromeric to KLK1. This distance might represent as many as 5.8 million base pairs or more than 100 genes.

	Selected Abbreviations and Acronyms

 

AFM = Association Française Contre les Myopathies CHLC = Cooperative Human Linkage Center HRC = histidine-rich calcium-binding protein ICCD = isolated cardiac conduction defect KLK1 = kallikrein 1 gene lod = log odds PCR = polymerase chain reaction PFHB1 = progressive familial heart block 1 RBBB = right bundle branch block

	Acknowledgments

 
The Lebanese part of this study was supported by CNRS of Lebanon and Ibrahim Yehia el-Hibri (Washington, DC). The French part of the research was supported by grants from Fondation de France, SESERAC, and Association Française Contre les Myopathies in addition to CNRS and INSERM support. Dr Bouvagnet wants to acknowledge the outstanding scientific training that he received in the B. Nadal-Ginard laboratory during his 3-year period in Boston. We are indebted to family members, without whose assistance this study would not have been possible. The technicians at Généthon, particularly A. Faure, are thanked for their decisive contribution to this work. Nabiha Salem is thanked for her careful technical assistance and Dr J. Laham for his useful comments. Richard McIndoe is warmly thanked for helping us to improve the editing of this manuscript.

Received December 30, 1994; accepted June 12, 1995.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 
1. Stephan E. Bloc auriculo-ventriculaire chez trois membres d'une même famille. Rev Med Moyen-Orient. 1954;11:246-249.

2. Stephan E. Bloc auriculo-ventriculaire familial. Arch Mal Coeur Vaiss. 1961;3:333-341.

3. Segall HN. Congenital arrhythmias and conduction abnormalities in a father and four children. Can Med Assoc J. 1961;84:1283-1296.

4. Combrink JM, Davis WH, Snyman HW. Familial bundle-branch block. Am Heart J. 1962;64:397-400. [Medline] [Order article via Infotrieve]

5. Husson GS, Blackman MS, Rogers MC, Bharati S, Lev M. Familial congenital bundle-branch system disease. Am J Cardiol. 1973;32:365-369. [Medline] [Order article via Infotrieve]

6. Brink AJ, Torrington M. Progressive familial heart block: two types. S Afr Med J. 1977;52:53-59. [Medline] [Order article via Infotrieve]

7. Stephan E. Hereditary bundle-branch system defect: survey of a family with four affected generations. Am Heart J. 1978;95:89-95. [Medline] [Order article via Infotrieve]

8. Stephan E. Hereditary bundle-branch system defect: a new genetic entity? Am Heart J. 1979;97:708-718. [Medline] [Order article via Infotrieve]

9. Stephan E, Aftimos G, Allam C. Familial fascicular block: histologic features of Lev's disease. Am Heart J. 1985;109:1399-1401. [Medline] [Order article via Infotrieve]

10. Hiss RG, Lamb LE. Electrocardiographic findings in 122043 individuals. Circulation. 1962;25:947-961. [Abstract/Free Full Text]

11. Gazes PC, Culler RM, Taber E, Kelly TE. Congenital familial cardiac conduction defects. Circulation. 1965;32:32-34. [Abstract/Free Full Text]

12. Spellberg RD. Familial sinus node disease. Chest. 1971;60:246-251. [Abstract/Free Full Text]

13. Sarachek NS, Leenard JJ. Familial heart block and sinus bradycardia: classification and natural history. Am J Cardiol. 1972;29:451-458. [Medline] [Order article via Infotrieve]

14. Rotman M, Triebwasser JH. A clinical follow-up study of right and left bundle branch block. Circulation. 1975;51:477-484. [Abstract/Free Full Text]

15. Waxman MB, Catching JD, Felderhof CH, Downar E, Silver MD, Abbott MM. Familial atrioventricular heart block: an autosomal dominant trait. Circulation. 1975;51:226-233. [Abstract/Free Full Text]

16. Laham J. Les Blocs de Branche en Clinique. Paris, France: Maloine;. 1985.

17. Calcaterra G, Puglisi R. Left axis deviation in healthy infants and children. Int J Cardiol. 1989;24:236-238. [Medline] [Order article via Infotrieve]

18. Saxena A, Shrivastava S, Dev V, Talwar KK, Kaul U, Tandon R. Congenital complete heart block in structurally normal hearts: a study of 44 cases. Indian Heart J. 1992;44:43-46. [Medline] [Order article via Infotrieve]

19. Lynch HT, Mohiuddin S, Sketch MH, Krush AJ, Carter S, Runco V. Hereditary progressive atrioventricular conduction defect: a new syndrome? JAMA. 1973;225:1465-1470. [Abstract/Free Full Text]

20. Esscher E, Hardell L-I, Michaëlsson M. Familial, isolated, complete right bundle-branch block. Br Heart J. 1975;37:745-747. [Abstract/Free Full Text]

21. McKusick VA. Mendelian Inheritance in Man: Catalogues of Autosomal Dominant, Autosomal Recessive and X-Linked Phenotypes. 9th ed. Baltimore, Md/London, England: The Johns Hopkins University Press; 1990.

22. Morgans CM, Gray KE, Robb GH. A survey of familial heart block. Br Heart J. 1974;36:693-696. [Free Full Text]

23. Greenspahn BR, Denes P, Daniel W, Rosen KM. Chronic bifascicular block: evaluation of familial factors. Ann Intern Med. 1976;84:521-525.

24. Kass S, MacRae C, Graber HL, Sparks EA, McNamara D, Boufoulas H, Basson CT, Baker PB III, Cody RJ, Fishman MC, Cox N, Kong A, Wooley CF, Seidman JG, Seidman CE. A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1. Nat Genet. 1994;7:546-551. [Medline] [Order article via Infotrieve]

25. Brink PA, Moolman JC, Ferreira A, de Jager T, Weymar HW, Martell RW, Torrington M, van der Merwe PL, Corfiel VA. Genetic linkage studies of progressive familial heart block, a cardiac conduction disorder. S Afr J Sci. 1994;90:236-240.

26. Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet. 1994;8:323-327. [Medline] [Order article via Infotrieve]

27. Gyapay G, Morisette J, Vignal A, Dib C, Fizames C, Millasseau P, Marc S, Bernardi G, Lathrop M, Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994;7:246-339. [Medline] [Order article via Infotrieve]

28. Pathak RK, Anderson RGW, Hofmann SL. Histidine-rich calcium binding protein, a sarcoplasmic reticulum protein of striated muscle cells, is also abundant in arteriolar smooth muscle cells. J Muscle Res Cell Motil. 1992;13:366-376. [Medline] [Order article via Infotrieve]

29. Rosenbaum MB. The hemiblocks: diagnosis criteria and clinical significance. Mod Concepts Cardiovasc Dis. 1970;39:141-146. [Medline] [Order article via Infotrieve]

30. Criteria committee of the New York Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 8th ed. Boston, Mass: Little, Brown & Co; 1979.

31. Feigenbaum H. Echocardiography. 3rd ed. Philadelphia, Pa: Lea & Febiger; 1985.

32. Vignal A. Nonradioactive multiplex procedure for genotyping of microsatellite markers. In: Adolph KW, ed. Methods in Molecular Genetics: Gene and Chromosome Analysis. San Diego, Calif: Academic Press Inc; 1993;1:211-221.

33. Hofmann SL, Topham M, Hsieh C-L, Francke U. cDNA and genomic cloning of HRC, a human sarcoplasmic reticulum protein, and localization of the gene to human chromosome 19 and mouse chromosome 7. Genomics. 1991;9:656-669. [Medline] [Order article via Infotrieve]

34. Buetow KH, Weber JL, Ludwigsen S, Scherpbier-Heddema T, Duyk GM, Sheffield VC, Wang Z, Murray JC. Integrated human genome-wide maps constructed using the CEPH reference panel. Nat Genet. 1994;6:391-393. [Medline] [Order article via Infotrieve]

35. Lathrop GM, Lalouel JM, Julier C, Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet. 1984;37:482-498.

36. Ghanem N, Dariavach P, Bensmna M, Chibani J, Lefranc G, Lefranc M-P. Polymorphism of immunoglobulin lambda constant region genes in populations from France, Lebanon and Tunisia. Exp Clin Immunogenet. 1988;5:186-195. [Medline] [Order article via Infotrieve]

37. Hofmann SL, Goldstein JL, Orth K, Moomaw CR, Slaughter CA, Braown MS. Molecular cloning of a histidine-rich Ca²⁺-binding protein of sarcoplasmic reticulum that contains highly conserved repeated elements. J Biol Chem. 1989;264:18083-18090. [Abstract/Free Full Text]

38. Graber HL, Unveferth DV, Baker PB, Ryan JM, Baba N, Wooley CF. Evolution of a hereditary cardiac conduction and muscle disorder: a study involving a family with six generations affected. Circulation. 1986;74:21-35. [Abstract/Free Full Text]

39. Brink PA, Ferreira A, Moolman JC, Hettie WW, van der Merwe PL, Corfield VA. Gene for progressive familial heart block type I maps to chromosome 19q13. Circulation. 1995;91:1633-1640.[Abstract/Free Full Text]

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