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Brachydactyly type A1 associated with unusual radiological findings and a novel Arg158Cys mutation in the Indian hedgehog (IHH) gene.

https://arctichealth.org/en/permalink/ahliterature150792
Source
Eur J Med Genet. 2009 Sep-Oct;52(5):297-302
Publication Type
Article
Author
Eva-Lena Stattin
Bjarne Lindén
Torsten Lönnerholm
Jens Schuster
Niklas Dahl
Author Affiliation
Department of Medical Biosciences, Medical and Clinical genetics, Umeå University, Umeå, Sweden. evalena.stattin@medbio.umu.se
Source
Eur J Med Genet. 2009 Sep-Oct;52(5):297-302
Language
English
Publication Type
Article
Keywords
Adult
Aged, 80 and over
Amino Acid Sequence
Amino Acid Substitution
Case-Control Studies
Chromosomes, Human, Pair 2
Chromosomes, Human, Pair 5
Cysteine - metabolism
DNA - genetics - isolation & purification
DNA Mutational Analysis
Female
Genes, Dominant
Genetic markers
Hedgehog Proteins - chemistry - genetics
Heterozygote
Humans
Limb Deformities, Congenital - genetics - radiography
Male
Microsatellite Repeats
Middle Aged
Models, Molecular
Molecular Sequence Data
Mutation, Missense
Pedigree
Phenotype
Polymorphism, Genetic
Protein Conformation
Protein Structure, Tertiary
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Sweden
Abstract
Brachydactyly type A1 (BDA1; MIM 112500) is characterized by shortness or absence of the middle phalanx of the hands and feet. The condition is caused by heterozygous mutations in the Indian hedgehog (IHH) gene or a yet unidentified gene on chromosome 5p13. We investigated six affected members of a large Swedish family segregating autosomal dominant brachymesophalangia. Affected individuals show hypoplasia of the ulnar styloid processes, ulna minus, osteoarthritis, normal length of all distal phalanges and shortening or absence of the middle phalanges. Stationary ossicles or sesamoid bones were observed at the metacarpal heads in all patients. Genetic analysis of the family showed that the IHH-gene was linked to the disease (Z(max) 3.42 at theta 0.00) and sequence analysis of IHH revealed a novel c.472C > T transition in all affected family members. The mutation results in a p.158Arg > Cys substitution located in the highly conserved amino-terminal domain of IHH. This domain is of importance for the interaction between IHH and the Patched receptor. Our combined findings add radiological findings to the BDA1 phenotype and confirm a critical functional domain of IHH.
PubMed ID
19464397 View in PubMed
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A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population.

https://arctichealth.org/en/permalink/ahliterature152673
Source
Am J Med Genet A. 2009 Mar;149A(3):380-6
Publication Type
Article
Date
Mar-2009
Author
Miriam Entesarian
Birgit Carlsson
Mahmoud Reza Mansouri
Eva-Lena Stattin
Eva Holmberg
Irina Golovleva
Hreinn Stefansson
Joakim Klar
Niklas Dahl
Author Affiliation
Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Source
Am J Med Genet A. 2009 Mar;149A(3):380-6
Date
Mar-2009
Language
English
Publication Type
Article
Keywords
Amniocentesis
Chi-Square Distribution
Chromosome Breakage
Chromosome Inversion
Chromosomes, Artificial, Bacterial
Chromosomes, Human, Pair 10
Cloning, Molecular
Cytogenetic Analysis
Gene Frequency
Genetic markers
Genetic Variation
Geography
Haplotypes
Heterozygote
Humans
In Situ Hybridization, Fluorescence
Microsatellite Repeats
Polymerase Chain Reaction
Population Groups
Sequence Analysis, DNA
Sweden
Abstract
We identified a paracentric inversion of chromosome 10 [inv(10)(q11.22q21.1)] in 0.20% of Swedish individuals (15/7,439) referred for cytogenetic analysis. A retrospective analysis of 8,896 karyotypes from amniocenteses in Sweden revealed a carrier frequency of 0.079% (7/8,896) for the inversion. Cloning and detailed analysis of the inversion breakpoint regions show enrichment for interspersed repeat elements and AT-stretches. The centromeric breakpoint coincides with that of a predicted inversion from HapMap data, which suggests that this region is involved in several chromosome 10 variants. No known gene or predicted transcript are disrupted by the inversion which spans approximately 12 Mb. Carriers from four non-related Swedish families have identical inversion breakpoints and haplotype analysis confirmed that the rearrangement is identical by descent. Diagnosis was retrieved in 6 out of the 15 carriers referred for cytogenetic analysis. No consistent phenotype was found to be associated with the inversion. Our study demonstrates that the inv(10)(q11.22q21.1) is a rare and inherited chromosome variant with a broad geographical distribution in Sweden.
PubMed ID
19213037 View in PubMed
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Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene.

https://arctichealth.org/en/permalink/ahliterature107125
Source
J Appl Physiol (1985). 2013 Nov;115(10):1423-32
Publication Type
Article
Date
Nov-2013
Author
Ulla-Britt Diamant
Farzad Vahedi
Annika Winbo
Annika Rydberg
Eva-Lena Stattin
Steen M Jensen
Lennart Bergfeldt
Author Affiliation
Department of Public Health and Clinical Medicine, Heart Centre, Umeå University, Umeå, Sweden;
Source
J Appl Physiol (1985). 2013 Nov;115(10):1423-32
Date
Nov-2013
Language
English
Publication Type
Article
Keywords
Action Potentials
Adrenergic beta-Antagonists - therapeutic use
Adult
Aged
Anti-Arrhythmia Agents - therapeutic use
Case-Control Studies
DNA Mutational Analysis
Female
Genetic Predisposition to Disease
Heart rate
Humans
KCNQ1 Potassium Channel - genetics - metabolism
Long QT Syndrome - drug therapy - genetics - metabolism - physiopathology
Male
Middle Aged
Mutation
Phenotype
Potassium - metabolism
Romano-Ward Syndrome - drug therapy - genetics - metabolism - physiopathology
Sweden
Time Factors
Vectorcardiography
Young Adult
Abstract
Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone.
PubMed ID
24052033 View in PubMed
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Exercise related sudden cardiac death (SCD) in the young - Pre-mortal characterization of a Swedish nationwide cohort, showing a decline in SCD among athletes.

https://arctichealth.org/en/permalink/ahliterature308837
Source
Resuscitation. 2019 11; 144:99-105
Publication Type
Journal Article
Date
11-2019
Author
Aase Wisten
Mats Börjesson
Peter Krantz
Eva-Lena Stattin
Author Affiliation
Department of Community Medicine and Rehabilitation, Sunderby Research Unit. Electronic address: aase.wisten@gmail.com.
Source
Resuscitation. 2019 11; 144:99-105
Date
11-2019
Language
English
Publication Type
Journal Article
Keywords
Adolescent
Adult
Athletes - statistics & numerical data
Child
Cohort Studies
Death, Sudden, Cardiac - epidemiology
Exercise
Female
Humans
Incidence
Male
Risk factors
Sweden - epidemiology
Symptom Assessment
Young Adult
Abstract
To study the frequency, etiology, and premortal abnormalities in exercise-related sudden cardiac death (SCD) in the young in Sweden.
All subjects with SCD in 10-35-year olds in Sweden during 2000-10, were included (n?=?514). Information about each case was retrieved from death certifications, autopsy- and medical records. The number of SCD in athletes was compared to national figures from 1992-99.
Exercise-related SCD occurred in 12% (62/514) of the SCD-population, a majority being men (56/62; 90%). Cardiopulmonary resuscitation (CPR) was started in 87% (54/62). In total, 48% (30/62), had a cardiac diagnosis, symptoms, family history and/or ECG-changes, before the fatal event. The most prevalent autopsy diagnosis was sudden arrhythmic death syndrome (15/62; 24%). The frequency of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) was significantly higher in exercise-related SCD compared to non-exertional SCD. Exercise-related SCD was more common in athletes (21/29) than in non-athletes (41/485) (P?
PubMed ID
31560990 View in PubMed
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Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing.

https://arctichealth.org/en/permalink/ahliterature119481
Source
BMC Cardiovasc Disord. 2012;12:95
Publication Type
Article
Date
2012
Author
Eva-Lena Stattin
Ida Maria Boström
Annika Winbo
Kristina Cederquist
Jenni Jonasson
Björn-Anders Jonsson
Ulla-Britt Diamant
Steen M Jensen
Annika Rydberg
Anna Norberg
Author Affiliation
Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden. evalena.stattin@medbio.umu.se
Source
BMC Cardiovasc Disord. 2012;12:95
Date
2012
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Child
Child, Preschool
Electrocardiography
Female
Genetic Testing
Genotype
Humans
Infant
Infant, Newborn
Long QT Syndrome - genetics
Male
Middle Aged
Mutation
Abstract
Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterised by prolongation of the QT interval on ECG, presence of syncope and sudden death. The symptoms in LQTS patients are highly variable, and genotype influences the clinical course. This study aims to report the spectrum of LQTS mutations in a Swedish cohort.
Between March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for LQTS genetic testing. We scanned five of the LQTS-susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) for mutations by DHPLC and/or sequencing. We applied MLPA to detect large deletions or duplications in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes. Furthermore, the gene RYR2 was screened in 36 selected LQTS genotype-negative patients to detect cases with the clinically overlapping disease catecholaminergic polymorphic ventricular tachycardia (CPVT).
In total, a disease-causing mutation was identified in 103 of the 200 (52%) index cases. Of these, altered exon copy numbers in the KCNH2 gene accounted for 2% of the mutations, whereas a RYR2 mutation accounted for 3% of the mutations. The genotype-positive cases stemmed from 64 distinct mutations, of which 28% were novel to this cohort. The majority of the distinct mutations were found in a single case (80%), whereas 20% of the mutations were observed more than once. Two founder mutations, KCNQ1 p.Y111C and KCNQ1 p.R518*, accounted for 25% of the genotype-positive index cases. Genetic cascade screening of 481 relatives to the 103 index cases with an identified mutation revealed 41% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death.
In this cohort of Swedish index cases with suspected LQTS, a disease-causing mutation was identified in 52% of the referred patients. Copy number variations explained 2% of the mutations and 3 of 36 selected cases (8%) harboured a mutation in the RYR2 gene. The mutation panorama is characterised by founder mutations (25%), even so, this cohort increases the amount of known LQTS-associated mutations, as approximately one-third (28%) of the detected mutations were unique.
Notes
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PubMed ID
23098067 View in PubMed
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Genetic screening in sudden cardiac death in the young can save future lives.

https://arctichealth.org/en/permalink/ahliterature265121
Source
Int J Legal Med. 2015 Jul 31;
Publication Type
Article
Date
Jul-31-2015
Author
Eva-Lena Stattin
Ida Maria Westin
Kristina Cederquist
Jenni Jonasson
Björn-Anders Jonsson
Stellan Mörner
Anna Norberg
Peter Krantz
Aase Wisten
Source
Int J Legal Med. 2015 Jul 31;
Date
Jul-31-2015
Language
English
Publication Type
Article
Abstract
Autopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds.
From January 2009 to December 2011, samples from 15 cases suffering SUD were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for molecular genetic evaluation. PCR and bidirectional Sanger sequencing of genes important for long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome type 1 (BrS1), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RYR2) was performed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions or duplications in the LQTS genes. Six pathogenic sequence variants (four LQTS and two CPVT) were discovered in 15 SUD cases (40 %). Ten first-degree family members were found to be mutation carriers (seven LQTS and three CPVT).
Cardiac ion channel genetic testing in autopsy-negative sudden death victims has a high diagnostic yield, with identification of the disease in 40 % of families. First-degree family members should be offered predictive testing, clinical evaluation, and treatment with the ultimate goal to prevent sudden death.
PubMed ID
26228265 View in PubMed
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High frequency of intermediary alleles in the HTT gene in Northern Sweden - The Swedish Huntingtin Alleles and Phenotype (SHAPE) study.

https://arctichealth.org/en/permalink/ahliterature305528
Source
Sci Rep. 2020 06 17; 10(1):9853
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Date
06-17-2020
Author
Jimmy Sundblom
Valter Niemelä
Maria Ghazarian
Ann-Sofi Strand
Ingvar A Bergdahl
Jan-Håkan Jansson
Stefan Söderberg
Eva-Lena Stattin
Author Affiliation
Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden. jimmy.sundblom@neuro.uu.se.
Source
Sci Rep. 2020 06 17; 10(1):9853
Date
06-17-2020
Language
English
Publication Type
Journal Article
Research Support, Non-U.S. Gov't
Keywords
Adult
Aged
Female
Gene Frequency
Humans
Huntingtin Protein - genetics
Huntington Disease - genetics
Male
Middle Aged
Phenotype
Sweden
Trinucleotide Repeats
Abstract
Trinucleotide (CAG) repeat expansions longer than 39 in the huntingtin (HTT) gene cause Huntington's disease (HD). The frequency of intermediate alleles (IA) with a length of 27-35 in the general population is not fully known, but studied in specific materials connected to the incidence of HD. The Swedish Huntingtin Alleles and Phenotype (SHAPE) study aims to assess the frequency of trinucleotide repeat expansions in the HTT gene in north Sweden. 8260 individuals unselected for HD from the counties of Norr- and Västerbotten in the north of Sweden were included. DNA samples were obtained and analysis of the HTT gene was performed, yielding data on HTT gene expansion length in 7379 individuals. A high frequency of intermediate alleles, 6.8%, was seen. Also, individuals with repeat numbers lower than ever previously reported (
PubMed ID
32555394 View in PubMed
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Low incidence of sudden cardiac death in a Swedish Y111C type 1 long-QT syndrome population.

https://arctichealth.org/en/permalink/ahliterature98529
Source
Circ Cardiovasc Genet. 2009 Dec;2(6):558-64
Publication Type
Article
Date
Dec-2009
Author
Annika Winbo
Ulla-Britt Diamant
Eva-Lena Stattin
Steen M Jensen
Annika Rydberg
Author Affiliation
Division of Pediatrics, Department of Clinical Sciences, Cardiology Heart Centre, Umeå University Hospital, Umeå, Sweden. annika.winbo@pediatri.umu.se
Source
Circ Cardiovasc Genet. 2009 Dec;2(6):558-64
Date
Dec-2009
Language
English
Geographic Location
Sweden
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Child
Child, Preschool
Death, Sudden, Cardiac - epidemiology
Female
Follow-Up Studies
Humans
Incidence
KCNQ1 Potassium Channel - genetics
Male
Middle Aged
Mutation, Missense
Pedigree
Romano-Ward Syndrome - epidemiology - genetics - mortality - pathology
Sweden - epidemiology
Young Adult
Abstract
BACKGROUND: A 10% cumulative incidence and a 0.3% per year incidence rate of sudden cardiac death in patients younger than 40 years and without therapy have been reported in type 1 long-QT syndrome. The Y111C-KCNQ1 mutation causes a severe phenotype in vitro, suggesting a high-risk mutation. This study investigated the phenotype among Y111C-KCNQ1 mutation carriers in the Swedish population with a focus on life-threatening cardiac events. METHODS AND RESULTS: We identified 80 mutation carriers in 15 index families, segregating the Y111C-KCNQ1 mutation during a national inventory of mutations causing the long-QT syndrome. Twenty-four mutation carriers
Notes
RefSource: Circ Cardiovasc Genet. 2009 Dec;2(6):537-9
PubMed ID
20031635 View in PubMed
Less detail

Origin of the Swedish Long QT Syndrome Y111C/KCNQ1 founder mutation.

https://arctichealth.org/en/permalink/ahliterature99940
Source
Heart Rhythm. 2010 Nov 30;
Publication Type
Article
Date
Nov-30-2010
Author
Annika Winbo
Ulla-Britt Diamant
Annika Rydberg
Johan Persson
Steen M Jensen
Eva-Lena Stattin
Author Affiliation
Umeå University, Department of Clinical Sciences, Pediatrics.
Source
Heart Rhythm. 2010 Nov 30;
Date
Nov-30-2010
Language
English
Publication Type
Article
Abstract
BACKGROUND: The Y111C/KCNQ1 mutation causes a dominant-negative effect in vitro albeit a benign clinical phenotype in a Swedish Long QT Syndrome population. OBJECTIVE: 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. Genealogical investigation was performed in 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 the ESTIAGE and DMLE computer softwares and regional population demographics data. RESULTS: All probands were traced back to a northern river valley region. A founder couple born in 1605/1614 connected 26/37 families. Haplotyped probands shared 2-14 (median 10) uncommon alleles, with frequencies ranging between 0.01-0.41 (median 0.16) in the controls. The age of the mutation was estimated to 24 generations (95% CI 18; 34), i.e. 600 years (95% CI 450; 850) if assuming 25 years per generation. The number of now living Swedish Y111C mutation-carriers was estimated to ~200-400 individuals for the mutation age span 22-24 generations and population growth rates 25-27%. CONCLUSIONS: The Y111C/KCNQ1 mutation is a Swedish LQTS founder mutation, introduced in the northern population approximately 600 years ago. The enrichment of the mutation was enabled by a mild clinical phenotype and strong regional founder effects during the population development of the northern inland. The Y111C/KCNQ1 founder population constitutes an important asset for future genetic and clinical studies.
PubMed ID
21129503 View in PubMed
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Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1 families.

https://arctichealth.org/en/permalink/ahliterature256812
Source
BMC Cardiovasc Disord. 2014;14:22
Publication Type
Article
Date
2014
Author
Annika Winbo
Eva-Lena Stattin
Charlotte Nordin
Ulla-Britt Diamant
Johan Persson
Steen M Jensen
Annika Rydberg
Author Affiliation
Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden. Annika.Winbo@pediatri.umu.se.
Source
BMC Cardiovasc Disord. 2014;14:22
Date
2014
Language
English
Publication Type
Article
Keywords
Adult
DNA Mutational Analysis
Electrocardiography
Female
Founder Effect
Gene Frequency
Genetic Predisposition to Disease
Haplotypes
Heart Arrest - epidemiology - genetics
Heredity
Heterozygote
Humans
Jervell-Lange Nielsen Syndrome - diagnosis - epidemiology - genetics - physiopathology - therapy
KCNQ1 Potassium Channel - genetics
Male
Molecular Biology
Mutation
Pedigree
Phenotype
Prognosis
Risk factors
Severity of Illness Index
Sweden - epidemiology
Time Factors
Young Adult
Abstract
The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome- JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide. In Sweden p.R518X accounts for the majority of JLNS cases and is the second most common cause of LQTS. Here we investigate the clinical phenotype and origin of Swedish carriers of the p.R518X mutation.
The study included 19 Swedish p.R518X index families, ascertained by molecular genetics methods (101 mutation-carriers, whereof 15 JLNS cases and 86 LQTS cases). In all families analyses included assessment of clinical data (symptoms, medications and manually measured electrocardiograms), genealogy (census records), haplotype (microsatellite markers) as well as assessment of mutation age and associated prevalence (ESTIAGE and DMLE computer software).
Clinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 ± 61 ms vs. 462 ± 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%, annual non-medicated incidence rate (aborted) cardiac arrest 4% vs. 0.04%).A common northern origin was found for 1701/1929 ancestors born 1650-1950. Historical geographical clustering in the coastal area of the Pite River valley was shown. A shared haplotype spanning the KCNQ1 gene was seen in 17/19 families. Mutation age was estimated to 28 generations (95% CI 19;41). A high prevalence of Swedish p.R518X heterozygotes was suggested (~1:2000-4000).
R518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.
Notes
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PubMed ID
24552659 View in PubMed
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16 records – page 1 of 2.