Progressive Familial Heart Block, Type Ib

A number sign (#) is used with this entry because of evidence that progressive familial heart block type IB (PFHB1B) is caused by heterozygous mutation in the TRPM4 gene (606936) on chromosome 19q13.

For a phenotypic description and a discussion of genetic heterogeneity of progressive familial heart block type I, see PFHB1A (113900).

Clinical Features

Brink and Torrington (1977) reported a 6-generation South African family of Portuguese and French ancestry with 261 known relatives, in which conduction defects segregated in an autosomal dominant pattern. Of 55 members in the last 3 generations who underwent electrocardiography, 31 had conduction abnormalities, including 16 with monofascicular right bundle branch block (RBBB), 3 with left anterior hemiblock, and 6 with complete heart block; another 6 individuals had a mildly prolonged QT interval or short PR interval without a Wolff-Parkinson-White (194200) pattern. The average age at which a pacemaker was implanted in the 3 successive generations decreased from 54.5 years in the fourth to 25 years in the fifth to 1 year of age in the sixth generation. Sudden cardiac death occurred in 22 individuals over the 3 generations, also at increasingly younger ages, dropping from an average of 50.7 years to 44.7 years to 12.3 years in the fourth, fifth, and sixth generations, respectively. Van der Merwe et al. (1986) and van der Merwe et al. (1988) provided follow-up information on the kindred reported by Brink and Torrington (1977) and documented the progressive nature of the disorder.

Stephan (1978) studied a Lebanese kindred with over 265 living descendants of a polygamous progenitor who was known to have had a slow pulse and syncope. Many examples of conduction defects, mainly right bundle branch block, left anterior hemiblock, bifascicular block and atrioventricular (AV) block, were found in his descendants. The abnormality was thought to be congenital, with a pedigree pattern consistent with autosomal dominant inheritance. However, 1 person presented with complete heart block at age 41.

Stephan et al. (1997) provided follow-up on the Lebanese kindred reported by Stephan (1978). They considered the most appropriate designation for this disorder to be 'hereditary bundle branch defect' (HBBD). Stephan et al. (1985) reported an autopsied case. There were over 400 descendants of the progenitor in 5 generations. Stephan et al. (1997) studied the evolution of the disorder in this kindred over a 2-decade period, described a variety of electrocardiographic abnormalities encountered in the family, and reassessed penetrance. A total of 396 persons had at least one clinical examination and electrocardiogram, of whom 47 were judged affected and 36 'indeterminate.' The conduction block may be overt in the first year of life, and among affected individuals there was a worsening of the conduction block in 5 to 15% of cases, leading to complete atrioventricular block and possibly to sudden death. A group of individuals had QRS anomalies in right precordial leads, possibly indicating partial right bundle branch block. A high proportion of these were identified as mutation carriers (the disorder in this family was shown to map to 19q) and about one-fifth of these patients evolved toward a complete fascicular block. By contrast, mutation carriers with a normal electrocardiogram remained normal. Mutation carriers demonstrated a conduction block significantly more often in males than females (75% and 50%, respectively). Brink et al. (1994, 1995) had found almost 100% penetrance in their South African family. Stephan et al. (1997) presented a table of penetrance values estimated from 9 other families as well as their own.

Liu et al. (2010) studied the large Lebanese kindred with autosomal dominant isolated cardiac conduction block, originally reported by Stephan (1978), as well as 2 French families with a variety of cardiac conduction blocks segregating in an autosomal dominant fashion. Altogether, there were 2 cases of isolated left axis deviation (LAD), 10 cases of complete right bundle branch block, 16 cases of incomplete RBBB, 15 cases of complete RBBB with LAD, 6 cases of complete RBBB with right axis deviation (RAD), and 7 cases of complete atrioventricular conduction block. Liu et al. (2010) observed 2 remarkable features in the 3 families: no family member had left bundle branch block (LBBB), complete or incomplete, and no other cardiac anomalies were found on repeated cardiac investigations, including echocardiogram, stress test, ambulatory electrocardiogram, and heart scintigraphy. The authors concluded that the 3 families shared an autosomal dominant disease resulting in any conduction block but LBBB, and no other cardiac anomalies.

Mapping

Brink et al. (1995) analyzed the large South African kindred reported by Brink and Torrington (1977) and demonstrated linkage to 19q13.2-q13.3. They pointed out that this kindred descended from an ancestor who emigrated from Portugal in 1696. It had been estimated that there may be between 1,000 and 9,000 gene carriers among his descendants. Maximum 2-point lod scores were 6.49 at theta = 0.0 for kallikrein (KLK1; 147910), 5.72 at theta = 0.01 for the myotonic dystrophy locus (DM; 160900), 3.44 at theta = 0.0 for the creatine kinase muscle-type locus (CKM; 123310), and 4.51 at theta = 0.10 for the apolipoprotein C2 locus (APOC2; 608083). Brink et al. (1995) noted that the gene for myotonin protein kinase, which is implicated as a cause of myotonic dystrophy, lies within this region and that myotonic dystrophy is a disease complicated by heart block and other conduction abnormalities; however, a recombination event ruled out the myotonic dystrophy locus from direct involvement with PFHB1B.

Using a genomewide screening approach with polymorphic (CA)n repeat markers in the Lebanese family originally described by Stephan (1978), de Meeus et al. (1995) obtained a maximum multipoint lod score of 7.18 at D19S604 on chromosome 19q13.3. Flanking loci D19S606 and D19S571 were excluded due to a recombination event in 3 affected individuals, narrowing the critical region to a 13-cM interval.

Using additional microsatellite markers in the Afrikaner kindred with progressive heart block originally reported by Brink and Torrington (1977), Kruse et al. (2009) narrowed the PFHB1B locus to a 0.5-Mb interval between markers D19S1059 and D19S604 on chromosome 19q13.33 containing approximately 25 genes.

Liu et al. (2010) analyzed polymorphic markers on chromosome 19q13 in 2 French families segregating autosomal dominant cardiac conduction defects as well as the large Lebanese kindred originally reported by Stephan (1978), and obtained a total multipoint lod score of 10.5, with a family-specific haplotype shared by all affected family members. The data narrowed the critical region to a 4-Mb interval flanked by CABP3 and D19S601.

Molecular Genetics

Kruse et al. (2009) analyzed the candidate gene TRPM4 in the Afrikaner kindred with progressive heart block originally reported by Brink and Torrington (1977) and identified a heterozygous missense mutation (E7K; 606936.0001) that segregated with the disease. Of 71 mutation carriers identified, 48 had pacemakers implanted. The mutation was not found in 230 ancestry-matched, unrelated Afrikaner controls or in 389 unrelated individuals of mixed European descent.

In the large Lebanese kindred originally reported by Stephan (1978) and 2 French families with autosomal dominant cardiac conduction defects mapping to chromosome 19q13, Liu et al. (2010) analyzed 12 candidate genes and identified 3 heterozygous missense mutations (606936.0002-606936.0004) in the TRPM4 gene that were found in all affected members of each family. The mutations were also detected in several family members with incomplete right bundle branch block or no block, consistent with incomplete penetrance; penetrance was calculated to be 75% for males and 54% for females. None of the variants was found in 300 ethnically matched chromosomes.

Stallmeyer et al. (2012) analyzed the TRPM4 gene in 160 unrelated patients with various types of inherited cardiac arrhythmias and identified 8 missense mutations in 8 patients (see, e.g., 606936.0002 and 606936.0004-606936.0006), including 5 (26.3%) of 19 patients with RBBB and 3 (11.5%) of 26 patients with atrioventricular block. No mutations were identified in patients with other types of cardiac arrhythmias. Noting the phenotypic variability in the mutation-positive patients, Stallmeyer et al. (2012) suggested that additional factors might modulate the disease phenotype in some patients.

Exclusion Studies

In selected affected members of the family originally reported by Brink and Torrington (1977), Bardien-Kruger et al. (2002) screened the coding region of the positional candidate gene KCNA7 by PCR-SSCP analysis and direct DNA sequencing and found no pathogenic sequence changes.