Novel compound heterozygous mutations in the KCNQ1 gene associated with autosomal recessive long QT syndrome (Jervell and Lange-Nielsen syndrome)

Abstract

Background: The Jervell and Lange-Nielsen syndrome (JLNS) is the autosomal recessive form of long QT syndrome (LQTS)--a familial cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. JLNS is associated with sensorineural deafness and has been shown to occur with homozygous mutations in KCNQ1 or KCNE1 in JLNS families in which QTc prolongation is inherited as a dominant trait. This study investigated the molecular pathology of a family with clinical evidence of JLNS.

Methods and results: Single-strand conformation polymorphism, denaturing high performance liquid chromatography, and DNA sequencing analyses were used to screen for KCNQ1 mutations. Novel compound heterozygous nonsense mutations R518X/Q530X in the C-terminus of KCNQ1 were identified in both affected dizygotic twins; both the parents and a sibling each carried only one of the mutant alleles and were asymptomatic with modestly prolonged QTc intervals (0.46, 0.50, and 0.45 seconds, respectively). These two nonsense mutations lead to premature termination of C-terminus with truncation of the postulated assembly domain.

Conclusion: Novel compound heterozygous nonsense mutations in C-terminus of KCNQ1 can cause JLNS.

Figures

Figure 1

Compound heterozygous nonsense mutations in C‐terminus of KCNQ1 cause JLNS. (a), JLNS affected individuals are shown as solid circles (females) or squares (males), unaffected JLNS individuals with only one allele of the mutation as wave (R518X) or stripe (Q530X) filled circles/squares, and controls as open circles/squares. The probands of the family are indicated by arrows. The KCNQ1 genotypes of each family member are indicated. SSCP analysis on 0.5X MDE gel of genomic PCR products is presented. The control and the mother show a normal migration pattern, with R518X mutation undetectable in this assay. Q530X mutation carriers present an additional band shown by an arrow. (b), Partial KCNQ1 sequences of mutation carriers: C to T substitutions at position 1552 (R518X), and at position 1588 (Q530X) in this family.

Figure 2

DHPLC mutation analysis of KCNQ1 exon12. DHPLC assay confirms the mutation (Q530X) detected by SSCP and identifies the mutation (R518X) missed by SSCP.

Figure 3

KCNQ1 mutations in JLNS patients. The positions of the mutations within the KCNQ1 channel identified in the family are illustrated.