Elsevier

Mayo Clinic Proceedings

Volume 74, Issue 11, November 1999, Pages 1088-1094
Mayo Clinic Proceedings

Original Article
Swimming, a Gene-Specific Arrhythmogenic Trigger for Inherited Long QT Syndrome

https://doi.org/10.4065/74.11.1088Get rights and content

Objective

To determine the genetic basis for long QT syndrome (LQTS) in a cohort of patients with a personal history or an extended family history of a swimming-triggered cardiac event.

Patients and Methods

After review of the Mayo Clinic unit medical record system, blood samples or archived autopsy tissue samples were obtained from a retrospective cohort of 35 cases diagnosed as having autosomal dominant LQTS. Exon-specific amplification by polymerase chain reaction and direct sequence analyses were performed on the entire KVLQTI gene.

Results

Six cases had a personal history or an extended family history of a near drowning or drowning. In all 6 cases, LQTS-causing mutations in KVLQT1 gene were identified: 3 deletion mutations, 2 donor splice site mutations, and 1 missense mutation. One of the mutations, a novel donor splicing defect, was determined by postmortern molecular analysis of a paraffin-embedded tissue block from a 12-year-old girl who died in 1976. Distinct KVLQT1 mutations were demonstrated in 3 of the remaining 29 cases. The overall frequency of KVLQT1 defects in LQTS was 100% (6/6) in those with and 10% (3/29) in those without a personal history or an extended family history of drowning or near drowning (P<.001).

Conclusion

Swimming appears to be a gene-specific (KVLQT1) arrhythmogenic trigger for LQTS. This study provides proof of principle that an unexplained drowning or near drowning may have a genetic basis.

Section snippets

Identification of a Swimming-Triggered LQTS Cohort

Thirty-nine probable cases of autosomal dominant LQTS were identified by review of the unit medical record system from 1975 to 1999. The Mayo Clinic unit medical record contains details of every outpatient visit to a physician's office or emergency department, every inpatient hospitalization, every laboratory result, all pathology reports, and all patient correspondence. In addition to the 2 near-drowning cases previously reported,13,14 review of the medical records as well as follow-up

Results

Every case of autosomal dominant LQTS with a personal history or an extended family history of drowning or near drowning had mutations in KVLQT1 (6/6; P<.001). Figure 1 summarizes some of the phenotypic information pertaining to this swimming cohort, including the 2 previously reported cases (numbered cases 1 and 5 herein). The specific LQTS mutations discovered in 5 of the 6 cases have been reported previously in other families with LQTS.13,14,18-21 A novel splice-site mutation was identified

Discussion

Less than 50% of LQTS is accounted for by mutations in the 5 cardiac ion channel genes, with mutations in the KVLQT1 gene being most common for these genotyped LQTS cases. However, only one fifth of all LQTS stems from a defective KVLQT1 substrate (P. J. Schwartz, MD, oral communication, October 1, 1999). There are obvious limitations in this assignment of LQTS disease gene frequencies, since the denominator of patients who have LQTS either manifest clinically or concealed genetically is

Acknowledgments

The authors wish to thank Carla M. Bell for her assistance with the chart reviews and to Erik J. Bergstralh for his statistical analysis. Moreover, we are indebted to these families with LQTS for their willingness to participate in this project. We hope that advances in our understanding of LQTS made possible by their involvement will prevent future tragedies such as those described herein.

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  • Cited by (0)

    Dr Ackerman was supported by a Howard W. Siebens Molecular Medicine Award from the Mayo Foundation and a Mayo Foundation clinical research award.

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