Open Access Highly Accessed Research article

Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing

Eva-Lena Stattin1*, Ida Maria Boström1, Annika Winbo2, Kristina Cederquist1, Jenni Jonasson1, Björn-Anders Jonsson1, Ulla-Britt Diamant3, Steen M Jensen3, Annika Rydberg2 and Anna Norberg1

Author Affiliations

1 Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden

2 Department of Clinical Sciences, Paediatrics, Umeå University, Umeå, Sweden

3 Heart Centre and Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

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BMC Cardiovascular Disorders 2012, 12:95  doi:10.1186/1471-2261-12-95

Published: 25 October 2012

Abstract

Background

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.

Methods

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).

Results

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.

Conclusion

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.

Keywords:
Arrhythmia; Long QT syndrome; Ion-channel; Founder mutation; Variant of unknown significance