Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers

Abstract

Mutations in the KCNQ1, HERG, SCN5A, minK and MiRP1 genes cause long QT syndrome (LQTS), of which there are two forms: the Romano Ward syndrome and the Jervell and Lange-Nielsen syndrome. We have performed DNA sequencing of the LQTS-associated genes in 169 unrelated patients referred for genetic testing with respect to Romano Ward syndrome and in 13 unrelated patients referred for genetic testing with respect to Jervell and Lange-Nielsen syndrome. A total of 37 different mutations in the 5 genes, of which 20 were novel, were identified. Among patients with the most stringent clinical criteria of Romano Ward syndrome, a mutation was identified in 71%. Twelve of the 13 unrelated patients referred for genetic testing with respect to Jervell and Lange-Nielsen syndrome were provided with a molecular genetic diagnosis. Cascade genetic screening of 505 relatives of index patients with molecularly defined LQTS identified 251 mutation carriers. The observed penetrance was 41%. Although caution must be exerted, the prevalence of heterozygotes for mutations in the LQTS-associated genes in Norway could be in the range 1/100-1/300, based on the prevalence of patients with Jervell and Lange-Nielsen syndrome.

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction

“…This may explain the absence of significant female predominance/transmission distortion recently reported in a Norwegian population where most of the identified LQT1 variants led to haploinsufficiency and a moderate channel dysfunction. 23 Nevertheless, there is no obvious link between the increased maternal transmission and the female predominance, these two observations may result from different mechanisms involving oocytes, spermatozoids, or other maternal tissues. As KCNQ1 is expressed in numerous organs and in different types of cells, variants that alter myocardial repolarization might also have important effects in other tissues and at early stages of development such as fertilization in which ion channels are crucially important.…”

Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation?

“…A later study of 182 families from two particular Long QT syndromes did not find the same distortion to the expected 50:50 Mendelian transmission. 10 Diseases caused by expansion of CAG repeats, such as Machado-Joseph disease 11,12 and spinocerebellar ataxia 7 13 are suggested to show a prevalence of transmission of the mutant allele, but again have conflicting reports. Investigating transmission at two CAG disease repeat loci, TRD was noted in male meioses in live-born offspring 11 and in sperm typing from MJD patients 14 and preferentially transmitted to live-born offspring by female carriers.…”

Genetic and Phenotypic Characterization of Community Hospital Patients With QT Prolongation

“…This illustrates the need for reevaluation before accepting previous claims of pathogenicity. Gln530* has previously been reported as the most prevalent pathogenic KCNQ1 variant in Norway,6 and it is most common in Telemark's neighbor district, Agder. It has consistently been reported as pathogenic in several populations 17.…”

“…Many at‐risk individuals are likely to be unaware of their status in light of the disorder's incomplete penetrance, variable expressivity, and unpredictable course 6, 26. The risk of life‐threatening cardiac events is highest in young adolescence, and identification of a pathogenic variant in an LQTS gene has the potential to prevent life‐threatening cardiac events in offspring or siblings 7, 27…”

“…Autosomal dominant is the most common inheritance pattern, and KCNQ1 (LQT1) harbors most genetic defects, followed by KCNH2 (LQT2) and SCN5A (LQT3) 6, 7. Penetrance is incomplete, and expression is variable within families; these factors complicate both interpretation of pathogenicity of sequence variants in LQTS genes and genetic counseling 8…”