An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort

Abstract

The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.1750G > A; p.Gly584Ser variant within the coding sequence of the KCNH2 gene implicated in Long QT Syndrome (LQTS), which occurred once in 500 whole genome sequences from this population, was investigated. Targeted sequencing of the KCNH2 gene in family members of the initial participant confirmed the presence of the sequence variant and identified two further members of the same family pedigree who shared the variant. Investigation of these three related participants for whom single nucleotide polymorphism (SNP) array genotypes were available allowed a unique shared haplotype of 1.22 Mb to be defined around this locus. Searching across the full cohort for this haplotype uncovered two additional apparently unrelated individuals with no known genealogical connection to the original kindred. All five participants with the defined haplotype were shown to share the rare variant by targeted Sanger sequencing. If this result were verified in a healthcare setting, it would be considered clinically actionable, and has been actioned in relatives ascertained independently through clinical presentation. The General Practitioners of four study participants with the rare variant were alerted to the research findings by letters outlining the phenotype (prolonged electrocardiographic QTc interval). A lack of detectable haplotype sharing between c.1750G > A; p.Gly584Ser chromosomes from previously reported individuals from Finland and those in this study from Shetland suggests that this mutation has arisen more than once in human history. This study showcases the potential value of isolate population-based research resources for genomic medicine. It also illustrates some challenges around communication of actionable findings in research participants in this context.

ArrhythmoGenoPharmacoTherapy

“…drugs (Chen et al, 2000;Mitcheson et al, 2000;Mehta et al, 2018) in connection with the pharmacotherapy of LQTS at genetic levels (Mehta et al, 2018;Yin et al, 2018;Cortez et al, 2019;Kerr et al, 2019). The voltage activated potassium channel (Kv11.1) is encoded by the humane-ether-a-go-go related gene (hERG), which predominantly contributes to the electrical activity of the myocardium (Vandenberg et al, 2012;Vasseur et al, 2019).…”

Contribution of common risk variants to multiple sclerosis in Orkney and Shetland

“…This idea was first suggested in 1981 by Compston, who implied that Orcadians in general may have higher frequencies of common risk variants [16]. [17][18][19]. A principal component plot of the three cohorts can also be found in Supplementary Fig.…”

“…This research used 97 MS cases and 2118 controls from the Orkney Complex Disease Study and the Northern Isles Multiple Sclerosis Study (NIMS; collectively referred to as ORCADES) as a sample of the Orkney population, 15 MS cases and 2090 controls from the Viking Health Study Shetland (VIKING) as a sample of the Shetland population and 30 MS cases and 8708 controls from Generation Scotland (GS) as a sample of the mainland Scotland population. ORCADES, VIKING and GS are cross-sectional, family-based cohorts that were established to become platform resources for the study of complex disease in Scotland, while the NIMS was established with the specific aim of studying MS. Data collection and genotyping for ORCADES, VIKING and GS has been fully described in previous research papers but has been summarised along with genotype and sample quality control (QC) steps in Supplementary Table 1 [ 17 – 19 ]. A principal component plot of the three cohorts can also be found in Supplementary Fig.…”

Same role but different actors: genetic regulation of post-translational modification of two distinct proteins

“…Written informed consent was given and the study was approved by the Ethics Committee of the Medical School, University of Split (approval id: 2181-198-03-04/10-11-0008). The Viking Health Study - Shetland (VIKING) is a family-based, cross-sectional study that seeks to identify genetic factors influencing cardiovascular and other disease risk in the population isolate of the Shetland Isles in northern Scotland 53 . Genetic diversity in this population is decreased compared to mainland Scotland, consistent with the high levels of endogamy.…”