Background-The electrocardiographic short QT-interval syndrome forms a distinct clinical entity presenting with a high rate of sudden death and exceptionally short QT intervals. The disorder has recently been linked to gain-of-function mutation in KCNH2. The present study demonstrates that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene. Methods and Results-A 70-year man presented with idiopathic ventricular fibrillation. Both immediately after the episode and much later, his QT interval was abnormally short without any other physical or electrophysiological anomalies. Analysis of candidate genes identified a g919c substitution in KCNQ1 encoding the K ϩ channel KvLQT1. Functional studies of the KvLQT1 V307L mutant (alone or coexpressed with the wild-type channel, in the presence of IsK) revealed a pronounced shift of the half-activation potential and an acceleration of the activation kinetics leading to a gain of function in I Ks . When introduced in a human action potential computer model, the modified biophysical parameters predicted repolarization shortening. Conclusions-We present an alternative molecular mechanism for the short QT-interval syndrome. Functional and computational studies of the KCNQ1 V307L mutation identified in a patient with this disorder favor the association of short QT with mutation in KCNQ1. Key Words: death, sudden Ⅲ genetics Ⅲ arrhythmia Ⅲ ion channels Ⅲ fibrillation, ventricular I n recent years, extensive progress has been made in unraveling the pathophysiology of the monogenic arrhythmia syndromes among which are long-QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. 1 The latest addition to this class of disorders is the description of families with a high rate of sudden death and exceptionally short QT intervals, 2 recently attributed to gain-of-function mutation in KCNH2. 3 In this study, we demonstrate that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene that encodes the KvLQT1 K ϩ channel, which, in association with the ␤-subunit IsK, forms the slow component of the cardiac delayed rectifier K ϩ current (I Ks ). 4 Methods Patient CharacteristicsA 70-year-old man was successfully resuscitated after a ventricular fibrillation episode. He had been without complaints up until then, and his family history was unremarkable. Physical examination revealed no abnormalities. His ECG is presented in Figure 1. Sinus rhythm was present with normal conduction intervals and a QT interval of 290 ms (QTc, 302 ms). Similarly short QT intervals were observed on every ECG up to 3 years of follow-up. Biochemical analysis at the time of admission, including echocardiography, exercise testing, coronary angiography, left (LV) and right ventricular (RV) angiography, scintigraphy, and ergonovine coronary spasm test, revealed no abnormalities. Nuclear LV ejection fraction was 49%. During electrophysiological study, no arrhythmias could be induced. The electrophysiology ...

The Hennekam syndrome is an infrequently reported heritable entity characterized by lymphedema, lymphangiectasia, and developmental delay. Here we add an additional 8 patients, and compare their findings to the 16 cases from the literature. The lymphedema is usually congenital, can be markedly asymmetrical, and, often, gradually progressive. Complications such as erysipelas are common. The lymphangiectasias are present in the intestines, but have also been found in the pleura, pericardium, thyroid gland, and kidney. Several patients have demonstrated congenital cardiac and blood vessel anomalies, pointing to a disturbance of angiogenesis in at least some of the patients. Facial features are variable, and are chiefly characterized, in a typical patient, by a flat face, flat and broad nasal bridge, and hypertelorism. Facial features are thought to mirror the extent of intrauterine facial lymphedema, or may be caused by lymphatic obstruction that affects the early migration of neural crest tissue. Other anomalies have included glaucoma, dental anomalies, hearing loss, and renal anomalies. The psychomotor development varies widely, even within a single family, from almost normal development to severe mental retardation. Convulsions are common. The existence of 10 familial cases, equal sex ratio, increased parental consanguinity rate (4/20 families), and absence of vertical transmission are consistent with an autosomal recessive pattern of inheritance. It seems likely that most (but not all) manifestations of the entity can be explained as sequences of impaired prenatal and postnatal lymphatic flow, suggesting that the causative gene(s) should have a major function in lymphangiogenesis.

Shwachman-Diamond syndrome (SDS) is