To investigate the clinical, genetic and cardiologic aspects of the Long QT Syndrome, a predominantly hereditary disease with episodic malignant arrhythmias and sudden death, and a demonstrated gene linkage in a large pedigree.

BACKGROUND:

The Long QT Syndrome (LQTS) is an infrequently occurring disorder of unknown cause in which affected individuals have an unusual electrocardiographic repolarization abnormality and a propensity to syncope and fatal ventricular tachyarrhythmias. The first family with LQTS was described by Jervell and Lange-Nielsen in 1957. Three sudden deaths occurred in four deaf children with QT prolongation; two other children and the parents were healthy with normal hearing and normal electrocardiograms. The findings were interpreted as a pattern of autosomal recessive inheritance. Subsequent reports identified LQTS families with normal hearing (Romano-Ward Syndrome) having a pattern of occurrence suggesting autosomal dominant inheritance.

DESIGN NARRATIVE:

Beginning in 1985, patients and their unaffected relatives were longitudinally followed in this multicenter study to develop and validate widely applicable clinical criteria for stratifying the risk of life-threatening arrhythmias. A population of genetically deaf students was surveyed to identify additional families with the unique association of Long QT Syndrome and congenital deafness in order to expand the data base for genetic studies in the recessive form of the disorder, the Jervell and Lange-Nielsen Syndrome. Pedigrees of selected Long QT Syndrome families were recorded to better understand the inheritance of the dominant form of the disorder, the Romano-Ward Syndrome. Genetic studies were conducted using human leukocyte antigen and other protein markers in order to investigate the gene locus for the autosomal dominant form of the syndrome. A select group of 30 patients and 30 unaffected relatives had 24-hour Holter monitoring, treadmill exercise, Valsalva maneuver and handgrip stress tests to determine if the patients had a unique cardiovascular response to autonomic dysfunction.

The study was renewed in 1993. The renewal had six aims. The first examined genetic heterogeneity in LQTS by testing for Harvey-ras-1 gene linkage in the existing well-characterized LQTS families with evidence of a major gene by segregation analysis; in LQTS families that did not show Harvey-ras- 1 linkage, a search for other closely linked genetic markers was initiated. The second aim explored by segregation analysis the likelihood that a second gene coexisted with the Harvey-ras-1 gene to explain a more malignant disease process in some LQTS families than in others. The third established normal standards for six quantitative repolarization parameters on a healthy population (n=4,000) using digitized ECG recordings, and biomedical and statistical techniques with adjustment for age, gender, race, and heart rate. The fourth aim continued the existing LQTS registry with ongoing enrollment of new families and follow-up of new and existing LQTS pedigrees (n=370 families) in order to provide a central repository for this disorder, especially as it related to the natural history of this disorder and ongoing genetic analyses. The fifth aim investigated the static (12-lead ECG) and dynamic (24-hour Holter ECG) aspects of ventricular repolarization in LQTS families showing Harvey-ras gene linkage to upgrade the ECG categorization of delayed repolarization using the Harvey-ras- 1 marker as the gold standard to identify affected and unaffected individuals. The sixth aim continued the prospective longitudinal follow-up study of LQTS families to better understand the long-term clinical course of this disorder; time-dependent survivorship analyses were performed to evaluate the effects of various clinical features, repolarization severity (QTc length), Harvey-ras-I gene linkage, and therapeutic efficacy with antiadrenergic therapy (if data permits) on outcome event rates (syncope and sudden death) in the LQTS probands.

The study has been renewed several times to: expand the pedigrees of LQTS families and family members enrolled in the registry; identify new LQTS gene mutations and expand the number of gene-identified affected and unaffected members in LQTS families with known gene mutations; investigate phenotype-genotype relationships in 200 genotyped families involving 1,200 affected and unaffected family members regarding the clinical course of LQTS, T-wave repolarization, triggering factors for cardiac events, and co-morbidity associations, all by genotype. The study remains a multicenter project with six clinical centers, a genetic component involving four molecular genetic labs, a statistical genetic component, a biostatistical component, and a coordinating center.

Probands are required to have clinical dx of LQTS. Family members are also invited to participate regardless of their dx.

As of the 2013 closeout report, 1329 probands with clinical dx of LQTS and members of their extended families have been enrolled in the LQTS Registry. By ECG classification, this includes 3420 probands and affected family members, 3533 unaffected family members, and 2105 family members with borderline QTc. Of those, 2125 have had mutations identified.