Romano-Ward long QT syndrome: Identification of a HERG mutation in a Taiwanese kindred

Romano-Ward syndrome is an autosomal dominant long-QT syndrome (LQTS) that predisposes affected individuals to sudden death from tachyarrhythmias. We investigated the molecular basis of LQTS in a Taiwanese kindred. Clinical a nd genetic analyses revealed that a mutation was linked to the human ether- a-go-go-related gene (HERG). The coding sequences and exon-intron borders o f HERG were amplified by means of polymerase chain reaction and subjected t o single-strand conformation polymorphism (SSCP) analysis. An exon with an aberrant SSCP pattern was cloned and sequenced to study the molecular lesio n. A C-->T transition in codon 614, leading to substitution of a valine for an alanine residue in the pore region of the HERG protein, was identified. Analysis with BsP1286I endonuclease digestion showed the mutation to be pr esent in all affected family members. Given that an unaffected paternal unc le had inherited the same allele from the grandfather as the proband's fath er, a de novo mutation had apparently occurred in the father and was transm itted to his offspring. In addition to offering presymptomatic genetic diag nosis, identification of the disease-causing mutation may suggest new thera peutic approaches for treatment and prevention of this cardiovascular disea se.