Origin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation

doi:10.1016/j.hrthm.2010.11.043

Heart Rhythm

Volume 8, Issue 4, April 2011, Pages 541-547

https://doi.org/10.1016/j.hrthm.2010.11.043 Get rights and content

Background

The Y111C/KCNQ1 mutation causes a dominant-negative effect in vitro but a benign clinical phenotype in a Swedish long QT syndrome population.

Objective

The purpose of this study was to investigate the origin (genealogic, geographic, genetic, and age) of the Y111C/KCNQ1 mutation in Sweden.

Methods

We identified 170 carriers of the Y111C/KCNQ1 mutation in 37 Swedish proband families. Genealogic investigation was performed for all families. Haplotype analysis was performed in 26 probands, 21 family members, and 84 healthy Swedish controls, using 15 satellite markers flanking the KCNQ1 gene. Mutation age was estimated using ESTIAGE and DMLE computer software and regional population demographic data.

Results

All probands were traced back to a northern river valley region. A founder couple born in 1605/1614 connected 26 of 37 families. Haplotyped probands shared 2–14 (median 10) uncommon alleles, with frequencies ranging between 0.01 and 0.41 (median 0.16) in the controls. The age of the mutation was estimated to 24 generations (95% confidence interval 18; 34), that is, 600 years (95% confidence interval 450; 850) assuming 25 years per generation. The number of now living Swedish Y111C mutation carriers was estimated to approximately 200–400 individuals for the mutation age span 22–24 generations and population growth rates 25%–27%.

Conclusion

The Y111C/KCNQ1 mutation is a Swedish long QT syndrome founder mutation that was introduced in the northern population approximately 600 years ago. Enrichment of the mutation was enabled by a mild clinical phenotype and strong regional founder effects during population development of the northern inland. The Y111C/KCNQ1 founder population constitutes an important asset for future genetic and clinical studies.

Introduction

Long QT syndrome (LQTS) is an autosomal dominant inherited arrhythmic disorder that can be caused by several hundred different mutations in at least 12 separate genes, most of which affect the function of cardiac ion channels.1, 2, 3 LQTS disease phenotype spans from asymptomatic carriership, with or without QT prolongation on the ECG, to syncope and sudden cardiac death from ventricular arrhythmia. Characteristically the LQTS-causing mutation is family specific, but founder mutations have been identified.2, 4 Founder mutations are mutations that are identical by descent and are enriched in a population derived from a limited gene pool. The nascence and development of a founder population is influenced by conditions such as environmental factors and socioethnic constructs as well as the specific properties of the mutation itself. The population development of Sweden encompassed a relative isolation of the river valleys spanning the northern part of the country from northwest to southeast, resulting in strong regional founder effects.⁵

We previously described the clinical phenotype of 80 Swedish carriers of the Y111C mutation in the KCNQ1 gene.⁶ The Y111C mutation, first reported in a North American female in the year 2000, has a strong dominant-negative electrophysiologic effect in vitro while presenting with a surprisingly mild clinical phenotype in Swedish carriers.6, 7, 8, 9

The aim of this study was to explore the possibility that the high occurrence of the Y111C/KCNQ1 mutation in the Swedish population is caused by a founder effect by investigating the origin (genealogic, geographic, genetic, and age) of the mutation.

Section snippets

Patients and families

Swedish Y111C/KCNQ1 index families were recruited from the regional LQTS Family Clinic in Umeå, a national inventory of LQTS patients, and national referrals to the accredited laboratory of the Department of Clinical Genetics, Umeå University Hospital. Probands (index cases) were defined as the first identified mutation-carrier in an index family. Index families were defined as the proband plus any mutation-carrier in the extended family identified through the cascade-screening process,

Results

We identified 170 mutation-carriers of the LQTS mutation Y111C/KCNQ1 in 37 apparently unrelated Swedish index families. Genealogic investigation, including geographic tracing of earliest known ancestors, was performed for all families. Haplotype analysis was performed for 26 of the 37 families. In 21 of these 26 families, two generations of mutation-carriers were available to aid in the identification of the disease-associated haplotype.

Discussion

We studied the origin of the Y111C/KCNQ1 founder mutation, an important cause of LQTS in Sweden. By investigating the genealogy and haplotype data of 37 Swedish Y111C probands, a shared geographic origin in the Ångerman River valley area was found, a founder couple born in 1605/1614 connecting 26 of 37 probands was identified, and traces of the original ancestral haploblock was seen in the DNA of all 26 haplotyped probands. Mutation dating placed the convergence of the Y111C bloodlines in the

Conclusion

The Y111C/KCNQ1 founder mutation probably was introduced in the inland of northern Sweden by early settlers in the 15th century. Subsequent population development within the relatively isolated river valleys caused strong founder effects that in combination with the mutations' mild phenotype probably enabled enrichment of this LQTS mutation in the northern Swedish population. This conclusion is supported by the presented clinical, epidemiologic, genealogic, and haplotype data. This large LQTS

Acknowledgments

We thank all of the families that participated in this study. We thank Dr. Emmanuelle Genin (Hopital Paul Brousse, Villejuif Cedex, France) for graciously allowing us to use the ESTIAGE computer software. We thank Susann Haraldsson, Medical Laboratory Assistant at the Department of Medical and Clinical Genetics, Umeå University Hospital, Umeå, for expert technical assistance. Illustrations for maps and figures were provided by illustrator Erik Winbo (erikwinbo.artworkfolio.com).

References (23)

P.J. Schwartz
The congenital long QT syndromes from genotype to phenotype: clinical implications
J Intern Med
(2006)
P.L. Hedley et al.
The genetic basis of long QT and short QT syndromes: a mutation update
Hum Mutat
(2009)
J.T. Lu et al.
Recent progress in congenital long QT syndrome
Curr Opin Cardiol
(2010)
P.A. Brink et al.
Of founder populations, long QT syndrome, and destiny
Heart Rhythm
(2009)
E. Einarsdottir et al.
The genetic population structure of northern Sweden and its implications for mapping genetic diseases
Hereditas
(2007)
A. Winbo et al.
Low incidence of sudden cardiac death in a Swedish Y111C type 1 long-QT syndrome population
Circ Cardiovasc Genet
(2009)
I. Splawski et al.
Spectrum of mutations in long-QT syndrome genesKVLQT1, HERG, SCN5A, KCNE1, and KCNE2
Circulation
(2000)
T. Jespersen et al.
Basolateral localisation of KCNQ1 potassium channels in MDCK cells: molecular identification of an N-terminal targeting motif
J Cell Sci
(2004)
S. Dahimene et al.
The N-terminal juxtamembranous domain of KCNQ1 is critical for channel surface expression: implications in the Romano-Ward LQT1 syndrome
Circ Res
(2006)
N. Hofman et al.
Active cascade screening in primary inherited arrhythmia syndromes
J Am Coll Cardiol
(2010)

P.J. Schwartz

Cascades or waterfalls, the cataracts of genetic screening are being opened on clinical cardiology

J Am Coll Cardiol

(2010)

Cited by (27)

Clinical Interpretation and Management of Genetic Variants
2020, JACC: Basic to Translational Science
Citation Excerpt :
As the population with the founder mutation drifts and migrates, the mutation aggregates within the population, although it remains exceedingly rare in the general population. The long QT syndrome in the European and South African populations is partly caused by founder mutations (40) (reviewed in Brink and Schwartz [41]). Recognizing that the genetic variants impart a gradient of effect sizes, whether functional or clinical, the focus has been to identify those variants that impart clinically discernible effects, and hence, play a role in the pathogenesis of the disease.
Genetic variants are major determinants of susceptibility to disease, response to therapy, and clinical outcomes. Advances in the short-read sequencing technologies, despite some shortcomings, have enabled identification of the vast majority of the genetic variants in each genome. The major challenge is in identifying the pathogenic variants in cardiovascular diseases. The yield of the genetic testing has been limited because of technological shortcomings and our incomplete understanding of the genetic basis of cardiovascular disorders. To advance the field, a shift to long-read sequencing platforms is necessary. In addition, to discern the pathogenic variants, genetic diseases should be considered as a continuum and the genetic variants as probabilistic factors with a gradient of effect sizes. Moreover, disease-specific physician-scientists with expertise in the clinical medicine and molecular genetics are best equipped to discern functional and clinical significance of the genetic variants. The changes would be expected to enhance clinical utilities of the genetic discoveries.
Genetic testing in Polynesian long QT syndrome probands reveals a lower diagnostic yield and an increased prevalence of rare variants
2020, Heart Rhythm
Citation Excerpt :
Specifically, an SCN5A gene variant associated with increased arrhythmia risk was found in 13% of African Americans and in none of the Asians or those of European ancestry.5 While the common occurrence of a variant tends to infer that it is benign, previous studies on LQTS founder populations have shown that certain pathogenic variants may become relatively common in a population subset.17–19 Founder effects occur when a small number of individuals are kept relatively isolated by factors such as regional isolation and/or there is preference to find spouses within a specific group.
New Zealand has a multiethnic population and a national cardiac inherited disease registry (Cardiac Inherited Disease Registry New Zealand [CIDRNZ]). Ancestry is reflected in the spectrum and prevalence of genetic variants in long QT syndrome (LQTS).
The purpose of this study was to study the genetic testing yield and mutation spectrum of CIDRNZ LQTS probands stratified by self-identified ethnicity.
A 15-year retrospective review of clinical CIDRNZ LQTS probands with a Schwartz score of ≥2 who had undergone genetic testing was performed.
Of the 264 included LQTS probands, 160 (61%) reported as European, 79 (30%) NZ Māori and Pacific peoples (Polynesian), and 25 (9%) Other ethnicities, with comparable clinical characteristics across ethnic groups (cardiac events in 72%; age at presentation 28±19 years; corrected QT interval 512±55 ms). Despite comparable testing (5.3±1.4 LQTS genes), a class III–V LQTS variant was identified in 35% of Polynesian probands as compared with 63% of European and 72% of Other probands (P<.0001). Among variant-positive CIDRNZ LQTS probands (n=148), Polynesians were more likely to have non-missense variants (57% vs 39% and 25% in probands of European and Other ethnicity, respectively; P=.005) as well as long QT syndrome type 1-3 variants not reported elsewhere (71% vs European 22% and Other 28%; P<.0001). Variants found in multiple probands were more likely to be shared within the same ethnic group; P<.01).
Genetic testing of Polynesian LQTS probands has a lower diagnostic yield, despite comparable testing and clinical disease severity. Rare LQTS variants are more common in Polynesian LQTS probands. These data emphasize the importance of increasing the knowledge of genetic variation in the Polynesian population.
Complexity of Molecular Genetics in the Inherited Cardiac Arrhythmias
2016, Ion Channels in Health and Disease
The cardiac channelopathies are a group of heritable disorders that are associated with arrhythmia and sudden cardiac death in the presence of a structurally normal heart. These disorders have been associated to mutations in genes that encode cardiac ion channel subunits or proteins that interact with, and regulate, ion channels. Despite the identification of the underlying genetic defect in affected families, challenges remain. The observations of large phenotypic variability and reduced penetrance among carriers of the same familial mutation point out that in addition to the primary genetic defect, other genetic and nongenetic factors modify the manifestation of the disease. The role of common genetic variants identified through genome-wide association studies of electrocardiographic parameters in the general population, which could act as genetic modifiers for the cardiac channelopathies, is now being explored. In this chapter we will discuss the genetic substrate and the increasing understanding of the genetic complexity of these disorders.
Routine ECG screening in infancy and early childhood should not be performed
2014, Heart Rhythm
Citation Excerpt :
Family screening in the Netherlands for familial hypercholesterolemia was assisted by a nurse making home visits56; 8–9 affected relatives were found per proband as opposed to 2.1 in New Zealand and 2.5 in Denmark.5 An LQTS registry in Sweden has achieved 5 per proband (A. Winbo, personal written communication, 20th August 2014).57 If 8 relatives per known familial LQTS proband are found in Auckland, New Zealand, 1 in 2000 of the population would have been detected.4
For all of us working in the field of inherited heart conditions, our ultimate aim is the prevention of sudden cardiac death in young people in our communities. We share the passion and drive to this aim with our colleagues Saul et al,¹ who write to advocate infant screening of infants for LQTS.
Although Saul et al aimed to write an unbiased review of the subject, they present data that support screening while underrepresenting evidence against it. Their illustrative Figure 1 is arguably misleading, presenting a graph of freedom from any cardiac event in symptomatic individuals with familial LQTS. We know that 87% of deaths from LQTS occur in those who were previously symptomatic.² This discussion, however, is not about symptomatic patients with LQTS; it is about the detection of presymptomatic individuals on a community level.
Our aim is to present evidence that has led us to oppose the conclusions and suggestions of their article. Most pediatric cardiologists do not wish to see ECG screening in infancy,³ and we are among them.
Saul et al state that there is sufficient evidence to propose ECG screening in infancy for LQTS. We disagree.
We disagree with this view for a number of reasons:(1) The effectiveness of such a program has not been evaluated in terms of outcome.(2)The ECG is an unreliable diagnostic tool with unacceptable reproducibility, specificity, and sensitivity (3)The adverse effects of overdiagnosing or underdiagnosing LQTS in thousands of individuals have not been evaluated. (4)There are no definitive criterion standard by which LQTS can be excluded once the possibility is raised, and in particular genetic testing is not sensitive or specific enough to do so. (5)There is a paucity of normative ECG and genetic data for non-Whites.
We propose what we believe is a more attractive alternative: the detection of LQTS in the community through an active multidisciplinary program to detect probands and screen family members, based around a clinical registry. This has already proven to be effective.4, 5, 6, 7, 8 If adequately resourced, this method will provide a quicker, more reliable, and more societally acceptable method to detect and manage families at risk, such that it might conceivably render population screening redundant.
Fabry disease: Evidence for a regional founder effect of the GLA gene mutation 30delG in Brazilian patients
2014, Molecular Genetics and Metabolism Reports
Citation Excerpt :
The small variations between the two different estimates are due to factors that cannot be measured precisely, such as identification of the true mutation rate of each X chromosome STR marker and of the true proportion between haplotypes assessed in this sample of individuals and the real distribution of haplotypes occurring in the population. In the interpretation of the results, we preferred to follow the approach presented by Winbo et al. [38], who proposed that the true estimation of the age of a mutation corresponds to the range of overlap of the confidence intervals between the estimates obtained using ESTIAGE and DMLE softwares. Following this approach, we can estimate that the GLA 30delG mutation occurred between 11 and 12 generations before the present, with a confidence interval between seven and 24 generations.
The Fabry disease is caused by mutations in the gene (GLA) that encodes the enzyme α-galactosidase A (α-Gal A). More than 500 pathologic variants of GLA have already been described, most of them are family-specific. In southern Brazil, a frequent single-base deletion (GLA 30delG) was identified among four families that do not recognize any common ancestral. In order to investigate the history of this mutation (investigate the founder effect, estimate the mutation age and the most likely source), six gene-flanking microsatellite markers of the X chromosome on the mutation carriers and their parents, 150 individuals from the same population and 300 individuals that compose the Brazilian parental populations (Europeans, Africans and Native Americans) were genotyped. A common haplotype to the four families was identified and characterized as founder. The age was estimated with two statistics software (DMLE 2.2 and ESTIAGE) that agreed with 11 to 12 generations old. This result indicates that the mutation GLA 30delG was originated from a single event on the X chromosome of a European immigrant, during the southern Brazil colonization between 1710 and 1740.
Cardiac channelopathies: Genetic and molecular mechanisms
2013, Gene
Citation Excerpt :
The average prevalence of LQTS has been reported to be 1:2500–1:5000 per individual (Goldenberg et al., 2008; Schwartz et al., 2009; Tester et al., 2006). Much higher LQTS prevalence numbers, 0.8–1.5% of the population, have been found in some ethnic groups with founder effects (Berge et al., 2008; Brink and Schwartz, 2009; Winbo et al., 2011). The second most frequent cardiac channelopathy is Brugada syndrome (BrS) (Benito et al., 2008), for which a prevalence of about 1:10,000 has been estimated in the USA, Europe and Russia (Campuzano et al., 2010; Dupliakov et al., 2007).
Channelopathies are diseases caused by dysfunctional ion channels, due to either genetic or acquired pathological factors. Inherited cardiac arrhythmic syndromes are among the most studied human disorders involving ion channels. Since seminal observations made in 1995, thousands of mutations have been found in many of the different genes that code for cardiac ion channel subunits and proteins that regulate the cardiac ion channels. The main phenotypes observed in patients carrying these mutations are congenital long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS) and variable types of conduction defects (CD). The goal of this review is to present an update of the main genetic and molecular mechanisms, as well as the associated phenotypes of cardiac channelopathies as of 2012.

View all citing articles on Scopus

: This research was supported by grants from the Swedish Heart-Lung Foundation, the Heart Foundation of Northern Sweden, and the Northern County Councils Cooperation Committee.

View full text

ClinicalGeneticOrigin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Patients and families

Results

Discussion

Conclusion

Acknowledgments

The congenital long QT syndromes from genotype to phenotype: clinical implications

J Intern Med

The genetic basis of long QT and short QT syndromes: a mutation update

Hum Mutat

Recent progress in congenital long QT syndrome

Curr Opin Cardiol

Of founder populations, long QT syndrome, and destiny

Heart Rhythm

The genetic population structure of northern Sweden and its implications for mapping genetic diseases

Hereditas

Low incidence of sudden cardiac death in a Swedish Y111C type 1 long-QT syndrome population

Circ Cardiovasc Genet

Spectrum of mutations in long-QT syndrome genesKVLQT1, HERG, SCN5A, KCNE1, and KCNE2

Circulation

Basolateral localisation of KCNQ1 potassium channels in MDCK cells: molecular identification of an N-terminal targeting motif

J Cell Sci

The N-terminal juxtamembranous domain of KCNQ1 is critical for channel surface expression: implications in the Romano-Ward LQT1 syndrome

Circ Res

Active cascade screening in primary inherited arrhythmia syndromes

J Am Coll Cardiol

Cascades or waterfalls, the cataracts of genetic screening are being opened on clinical cardiology

J Am Coll Cardiol

Clinical
Genetic
Origin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation