Autosomal recessive long QT syndrome, type 1 in eight families from Saudi Arabia

Abstract

BackgroundOne of the most common primary cardiac arrhythmia syndromes is autosomal dominant long QT syndrome, type 1 (LQT1), chiefly caused by mono‐allelic mutations in the KCNQ1 gene. Bi‐allelic mutations in the KCNQ1 gene are causal to Jervell and Lange‐Nielsen syndrome (JLNS), characterized by severe and early‐onset arrhythmias with prolonged QTc interval on surface ECG and sensorineural deafness. Occasionally, bi‐allelic mutations in KCNQ1 are also found in patients without any deafness, referred to as autosomal recessive long QT syndrome, type 1 (AR LQT1).MethodsWe used Sanger sequencing to detect the pathogenic mutations in KCNQ1 gene in eight families from Saudi Arabia with autosomal recessive LQT1.ResultsWe have detected pathogenic mutations in all eight families, two of the mutations are founder mutations, which are c.387‐5T>A and p.Val172Met/p.Arg293Cys (in cis). QTc and cardiac phenotype was found to be pronounced in all the probands comparable to the cardiac phenotype in JLNS patients. Heterozygous carriers for these mutations did not exhibit any clinical phenotype, but a significant number of them have sinus bradycardia.ConclusionTo the best of our knowledge, this is the first description of a large series of patients with familial autosomal recessive LQT, type 1. These mutations could be used for targeted screening in cardiac arrhythmia patients in Saudi Arabia and in people of Arabic ancestry.

KCNQ1 and Long QT Syndrome in 1/45 Amish

“… 34 In the Saudi Arabian founder mutation (c.387-5T>A), there was a high incidence of homozygotes likely due to endogamy. 35 The p.T224M variant in the Amish has a higher prevalence (1/45) than these other founder variants, with a smaller effect size on QTc (20.2 ms/allele) and possibly lower morbidity. To date, we have not found any p.T224M homozygotes but speculate that some of the stillbirths reported to us could have been homozygotes.…”