The mutational spectrum of Jervell and Lange-Nielsen syndrome: insights from highly consanguineous families

Background/ObjectivesJervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive disease caused by mutations in KCNQ1 or KCNE1. It is characterized by prolonged QT interval on electrocardiogram, deafness and an increased risk of sudden cardiac death (SCD) (25%). Given the high consanguinity rate (35%) in the Middle East and North Africa region (MENA), an enrichment of JLNS is expected, providing a powerful opportunity to identify ancestry-specific genetic determinants. We report genetic data from the largest MENA JLNS cohort analyzed to date. MethodsProspective Egyptian JLNS families and ancestry-matched controls were recruited to Aswan Heart Centre for clinical phenotyping and genetic testing for genes with reported roles in inherited cardiac conditions (Illumina). Variants were classified according to the ACMG/AMP guidelines. ResultsWe followed up 57 patients (25 males and 32 females; mean age at enrollment: 5.8 years) from 47 families for four years. Consanguinity was reported in 76.2% of families with complete family data. All of the sequenced patients (n=52) harbored homozygous variants in KCNQ1 (n=51) or KCNE1 (n=1). Among these variants, 90.4% were truncating. The majority of KCNQ1 variants were located in the c-terminal domain. No significant differences in the clinical parameters were observed between carriers of different domains of the KCNQ1 protein, as well as between carriers of truncating variants versus nontruncating variants. A novel, recurring KCNQ1 variant (c.912G>A) was identified in 11 Egyptian patients from 10 families (21.2%), suggesting that it could be an Egyptian-specific founder mutation. ConclusionVariants discovered in this underrepresented population add to the mutational spectrum of JLNS and uncover ancestry-specific genetic determinants of disease. Expanding the cohort will provide important genetic and mechanistic insights into the global understanding of inherited arrhythmia syndromes.