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

Futema, M; Bird, M; Haeger, A; Pinder, E; O’Rourke, A; Behr, ER; Humphries, SE

Journal article

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

Abstract:: Background: Heterozygous Familial Hypercholesterolaemia (HeFH) is caused by pathogenic variants in LDLR, APOB, APOE or PCSK9, 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. Methods: Variants in LDLR, APOB, APOE and PCSK9 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. Results: 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: LDLR 67%, APOB 26.5%, APOE 3.5% and PCSK9 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. Conclusions: 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.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Futema, M., Bird, M., Haeger, A., Pinder, E., O’Rourke, A., Behr, E. R., & Humphries, S. E. (2026). Frequency of familial hypercholesterolaemia-causing genetic variants in the 100 000 Genomes Project cohort: whole genome sequencing analyses of 77 260 participants. Journal of Medical Genetics, jmg-2025–111201.

MLA Style

Futema, M, et al. “Frequency of Familial Hypercholesterolaemia-Causing Genetic Variants in the 100 000 Genomes Project Cohort: Whole Genome Sequencing Analyses of 77 260 Participants.” Journal of Medical Genetics, 2026, pp. jmg-2025–111201.

Chicago Style

Futema, M, M Bird, A Haeger, et al. 2026. “Frequency of Familial Hypercholesterolaemia-Causing Genetic Variants in the 100 000 Genomes Project Cohort: Whole Genome Sequencing Analyses of 77 260 Participants.” Journal of Medical Genetics, jmg-2025–111201.
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