MD; for the EUROGENE Heart Failure ProjectBackground-Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice. Methods and Results-The entire coding sequences of 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC, and TNNC1) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients (Ϸ63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (MYBPC3) and ␤-myosin heavy chain (MYH7) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (Pϭ0.036). Moreover, a mutation was found in 15 of 25 index cases with "sporadic" hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients. Conclusion-These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing MYBPC3 and MYH7 and then focus on TNNI3, TNNT2, and MYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened. (Circulation.

Abstract-Heterozygous mutations in genes encoding cardiac ionic channel subunits KCNQ1, HERG, SCN5A, KCNE1, and KCNE2 are causally involved in the dominant form of long-QT syndrome (LQTS) while homozygous mutations in KCNQ1 and KCNE1 cause LQTS with or without congenital deafness. In addition, two homozygous HERG mutations have been associated with severe LQTS with functional atrioventricular conduction anomalies in young children. A 2:1 atrioventricular block (AVB) with a major QTc prolongation (526 ms) was evidenced in a 5-year-old boy referred for syncope and seizure. LQTS was diagnosed and beta-blocking therapy initiated leading to normal atrioventricular conduction. Electrophysiological study provided support that location of the AVB was infra-Hisian. DNA analysis was performed in the proband and in asymptomatic family members. A novel missense mutation, V1777M, in the early C-terminal domain of SCN5A was identified. The proband was homozygous while the parents and two siblings were heterozygous carriers. Homozygote and heterozygote expression of the mutant channels in tsA201 mammalian cells resulted in a persistent inward sodium current of 3.96Ϯ0.83% and 1.49Ϯ0.47% at Ϫ30 mV, respectively, which was dramatically reduced in the presence of tetrodotoxin. This study provides the first evidence for a homozygous missense mutation in SCN5A and suggests that LQTS with functional 2:1 AVB in young children, a severe phenotype associated with bad prognosis, may be caused by homozygous or heterozygous compound mutations not only in HERG but also in SCN5A. T he congenital long-QT syndrome (LQTS) is a potentially lethal cardiac disease caused by mutations in specific ion channels. Heterozygosity for a mutation in the potassium channel genes HERG (LQT2) and KCNE2 (LQT6) causes defects in the rapid component of the delayed rectifier I Kr , whereas mutations in KCNQ1 (LQT1) and KCNE1 (LQT5) cause defects in the slow component of the delayed rectifier I Ks . 1 Mutations in SCN5A cause a persistent cardiac sodium current that is responsible for LQT3. 2 This form has been associated with a lower rate of cardiac events but a higher rate of lethal events. 3 Homozygosity for mutations in KCNQ1 and KCNE1 have been associated with the recessively inherited Jervell and Lange-Nielsen syndrome, in which QT prolongation is associated with a bilateral neurosensitive deafness. 4 -6 Nevertheless, several LQT1 recessive variants without deafness have also been described. 7,8 Recently, homozygosity for HERG mutations associated with atrioventricular (AV) conduction disturbances have been reported. 9,10 We describe the first case of an LQTS patient with functional 2:1 AV block (AVB) due to a homozygous missense mutation in SCN5A. Materials and Methods Clinical DataThe proband of a 9-member family was referred for syncope. The father originated from Senegal and the mother from Guinea without any known consanguinity. Both parents and the 7 children underwent clinical evaluation and cardiovascular examination, including a 12-lead ECG (ECG...