In 5 kindreds (K1807, K161, K162, K163, and K164) with 47 members affected by LQT1 (192500), Wang et al. (1996) demonstrated a GCG (ala) to GTG (val) transversion in codon 341 of the KVLQT1 gene. The mutation segregated with disease in the families and was not found in DNA samples from 200 unrelated controls.
In affected members of a South African family of Afrikaner origin with LQT (pedigree 166), de Jager et al. (1996) identified heterozygosity for the A341V mutation in the KVLQT1 gene. Haplotype analysis of this family and 4 Afrikaner families previously studied by Wang et al. (1996) (pedigrees 161, 162, 163, and 164) revealed that all 5 families shared a common haplotype, indicating a founder effect. Noting differences in severity of disease between the 2 largest families, 161 and 162, de Jager et al. (1996) suggested that the spectrum of clinical symptoms might reflect the influence of different modulating environmental or genetic backgrounds on expression of the same mutant allele.
Russell et al. (1996) detected this mutation in the spontaneous occurrence of LQT in monozygotic twin offspring of normal parents. This mutation would be expected to encode a potassium channel with altered conductance properties. They noted that mutations at this same nucleotide have been observed in 8 of 19 LQT families determined to have KVLQT1 mutations to that time, suggesting a mutation hotspot. (This variant used to be known as ALA212VAL and ALA246VAL.)
Brink et al. (2005) studied an LQTS founder population (SA-A341V) consisting of 22 apparently unrelated South African kindreds of Afrikaner origin (including pedigrees 161, 162, 163, 164, and 166), all of which could be traced to a single founding couple of mixed Dutch and French Huguenot origin who married in approximately 1730. Comparing the Afrikaner patients to the general LQT1 population, Brink et al. (2005) found that the SA-A341V group exhibited a significantly more severe form of the disease, with an earlier age of onset, longer QTc intervals, and an increased incidence of first cardiac event by age 20 years. Functional analysis in CHO cells demonstrated that coexpression of the A341V mutant reduced the magnitude of wildtype channel repolarizing current by approximately 50%, indicating that the mutation exerts a dominant-negative effect.
Modifier Effects of Variation in the AKAP9 Gene
In 349 members of a South African founder population of Afrikaner origin with LQT1, 168 of whom carried an identical-by-descent A341V mutation, de Villiers et al. (2014) genotyped 4 SNPs in the AKAP9 gene (604001) and found statistically significant associations between certain alleles, genotypes, and haplotypes and phenotypic traits such as QTc interval length, risk of cardiac events, and/or disease severity. De Villiers et al. (2014) stated that these results clearly demonstrated that AKAP9 contributes to LQTS phenotypic variability; however, the authors noted that because these SNPs are located in intronic regions of the gene, functional or regulatory variants in linkage disequilibrium with the SNPs were likely to be responsible for the modifying effects.
