Of founder populations, long QT syndrome, and destiny

Abstract

Founder populations, characterized by a single ancestor affected by long QT syndrome (LQTS) and by a large number of individuals and families who all are related to the ancestor and thereby carry the same disease-causing mutation, represent the ideal human model for studying the role of "modifier genes" in LQTS. This article reviews some of the fundamental concepts related to founder populations and provides the necessary historical background to understand why so many can be found in South Africa. The focus then moves to a specific LQT1 founder population, carrier of the A341V mutation, that has been studied extensively during the last 10 years and has provided a significant amount of previously unforeseen information. These novel findings range from an unusually high clinical severity not explained by the electrophysiologic characteristics of the mutation, to the importance of tonic and reflex control of heart rate for risk stratification, to the identification of the first modifier genes for clinical severity of LQTS.

Figure 1

The ancestors of current living A341V carriers could be traced to children of the union between Susanna Swart, daughter of Pieter Swart and Sara du Buys, and Dirk Uys. They were residing in the Southern Cape in an area within 200 km from Cape Town where until about the end of the 19^th century all obligate A341V carriers can be traced to.

Figure 2

Record of the baptism of Johannes Swart, son of Pieter Swart and Sara (du) Buys, in 1722 (page 100 of the baptismal book) [highlighted in yellow] by the “scriba” (church secretary) of the Dutch Reformed Church in Stellenbosch, the second oldest European town in South Africa after Cape Town. Two of the Swart children were baptised here.

Figure 3

Unadjusted Kaplan Meier estimate of the cumulative event-free survival in the non-SA and SAA341V groups. Any cardiac event (syncope, cardiac arrest or LQTS-related sudden cardiac death), whichever occurred first, was considered from birth through age 40 years and before β-blocker therapy. Numbers at risk are indicated. (From ref. 29)

Figure 4

Unadjusted Kaplan Meier estimate of the cumulative event-free survival (any first event) in the whole (non-SA + SA) A341V population plotted versus the LQT1 non-A341V group. Any cardiac event, whichever occurred first, was considered from birth through age 40 and before β-blocker therapy. Numbers at risk are indicated. (From ref. 29)

Figure 5

Unadjusted Kaplan Meier estimate of the cumulative event free survival (any first event) only in patients with LQT1 secondary to dominant negative KCNQ1 mutations: the two A341V groups are plotted versus the LQT1 non-A341V group. Any cardiac event, whichever occurred first, was considered from birth through age 40 and before β-blocker therapy. Numbers at risk are indicated. (From ref. 29)

Figure 6

Unadjusted Kaplan Meier estimate of the cumulative probability of a cardiac event (syncope, cardiac arrest or LQTS-related sudden death, whichever occurred first) in the LQT1 population from the U.S.-Netherlands-Japan collaborative study (8). Carriers of A341V mutation are compared with all the other LQT1 non-A341V patients. Superimposed is the curve representing the cumulative probability of a first cardiac event in the entire (SA+ non-SA) A341V population from the present study. Numbers at risk are indicated. (From ref. 29)

Figure 7

Percentage of symptomatic patients with a basal QTc < 500 ms in each tertile of heart rate. (From ref. 28)

Figure 8

Differential risk for arrhythmic events among 56 MCs according to resting heart rate off- β-blockers and QTc. The dashed horizontal line represents the predefined cut-off for QTc (≤ or >500 ms) whereas the dashed vertical line corresponds to the first tertile (≤60 bpm) of the heart rate values distribution. With a QTc > 500 ms all but one patient have symptoms. When the QTc is < 50 ms the level of heart rate plays a major role as while above 60 b/min the probability of events is 80% vs 38% when heart rate is bellow 60 b/min. (Modified from ref. 31)

Figure 9

BRS values off-βB in the entire group under study aged 26–47 years (9A), in MCs and in non-MCs (9B), and in symptomatic and asymptomatic MCs (9C). Mean and standard deviation are shown for each subgroup. The dashed horizontal line represents the lower tertile of BRS values. (From ref. 31)

Figure 10

BRS values off-βB in subjects aged 26–47 years (MCs and non-MCs), according to the specific genotype. Group 1: subjects with the ADRA2C-Del322-325 and subjects homozygous for ADRB1-R389. Group 2: subjects without ADRA2C-Del322-325 and not homozygous for the ADRB1-R389 allele. The solid horizontal line represents the upper tertile of BRS values. (From ref. 31)