Long QT Syndrome-Population Genetics and Cardiac Studies

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.