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.

Figure 1

Extracts from two multi-generational VIKING pedigrees. (A) Excerpt from a pedigree containing more than 30 genotyped participants, Family A. The initial participant with WGS (ID1) is indicated by an arrow and his two carrier relatives (ID2 and ID3) in the pedigree are shaded in black. (B) Excerpt from a second pedigree (Family B) containing 10 genotyped participants. The two participants identified by haplotype analysis, ID4 and ID5, are shaded in black. Other genotyped VIKING participants in each family are shown in green, and participants with WGS data are indicated. Family members not in the research cohort are represented in lighter shading. There are many other family members not shown. Obligate carriers of the rare variant are filled in dark grey. Values below each individual are their measured QTc interval.

Figure 2

Analysis of shared haplotypes using phased genotypes. The figure shows the genomic positions of informative SNPs in a 1.22 Mb region of Chromosome 7, with the rs199473428 SNP indicated by a grey line (arrowed). Haplotypes (H1 and H2) of the participant with WGS data (ID1) and his two relatives (ID2 and ID3) in Family A are shown. The carrier haplotype was identified as H2 of ID1, and H1 of individuals ID2 and ID3. The extent of sharing goes beyond the 1.22 Mb window shown.

Figure 3

(A) Genomic sharing between individuals ID1 in Family A and ID5 in Family B. Chromosomes (autosomes) 1 to 22 are shown horizontally, with the scale in megabases (Mb). (B) Comparison of the genomic sharing on chromosome 7 between ID1 and each of the other four rare variant heterozygotes. The haplotype has been broken down by recombination, comparing kindred A (ID1, ID2, ID3) and kindred B (ID4, ID5). In both parts of the Figure, segments of identity-by-descent (IBD1) are indicated in blue. The 4.93 Mb segment shared by all five heterozygotes on chromosome 7q, that includes the KCNH2 locus at 150 Mb, is marked with a *. Regions with no identity-by-descent (IBD0) are in white and centromere regions are shown as gaps.