Frequency of familial hypercholesterolaemia-causing genetic variants in the 100 000 Genomes Project cohort: whole genome sequencing analyses of 77 260 participants

<h4>Background</h4>Heterozygous Familial Hypercholesterolaemia (HeFH) is caused by pathogenic variants in <i>LDLR</i>, <i>APOB</i>, <i>APOE</i> or <i>PCSK9</i>, leading to elevated low-density lipoprotein-cholesterol and increased cardiovascular risk. In the UK, HeFH affects ~1 in 288 individuals. The 100 000 Genomes Project (100KGP) generated whole genome sequencing (WGS) data from >85 000 participants recruited primarily with cancer or rare inherited disorders. We analysed WGS data to assess the prevalence and spectrum of FH-causing variants.<h4>Methods</h4>Variants in <i>LDLR</i>, <i>APOB</i>, <i>APOE</i> and <i>PCSK9</i> were extracted from 100KGP WGS data and annotated using expert-reviewed ClinGen curation. Demographic, ancestry and linked health records were incorporated. Analyses were restricted to unrelated individuals.<h4>Results</h4>Among 54 818 unrelated participants, 167 were heterozygote for an FH-causing variant, giving a prevalence of 1:328 (95% CI 1:285 to 1:386). Prevalence was similar across ancestries, including African (1:388) and South Asian (1:276). Variant distribution was: <i>LDLR</i> 67%, <i>APOB</i> 26.5%, <i>APOE</i> 3.5% and <i>PCSK9</i> 3%. Two individuals carried two FH variants, consistent with homozygous FH. Among 22 442 genetic relatives, 77 also carried an FH variant. Of all variant carriers, 53% were female, mean age at recruitment was 41.3 years, with 43 younger than 18 years, and 54.3% had documented hypercholesterolaemia.<h4>Conclusions</h4>The prevalence and gene distribution of FH-causing variants in 100KGP are consistent with UK estimates. Differences in variant spectrum across ancestries were observed; however, FH prevalence was similar. Participants who consented to the return of actionable findings were informed, providing direct clinical benefit from genomic research.