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Cascade Screening for Familial Hypercholesterolemia in South Africa: The Wits FIND-FH Program
Frederick J Raal1, El Mustapha Bahassi2, Belinda Stevens1
1Department of Medicine, Stein Center for FH, Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (F.J.R., B.S.).
Insights
Familial hypercholesterolemia (FH) screening in South Africa identified a high prevalence, with genetic confirmation in 60% of diagnosed cases. The Wits FIND-FH program is also detecting FH in Black African populations.
Area of Science:
- Cardiovascular Genetics
- Public Health Genomics
- Genetic Epidemiology
Background:
- Familial hypercholesterolemia (FH) is a significant cause of premature atherosclerotic cardiovascular disease.
- Gene founder effects lead to high FH prevalence in specific South African ancestries (Afrikaner, Jewish, Indian).
- Limited data exists on FH prevalence in Black African populations.
Purpose of the Study:
- To establish a systematic program (Wits FIND-FH) for identifying South African families with FH.
- To determine FH prevalence across diverse South African populations.
- To genetically characterize FH cases and identify causative variants.
Main Methods:
- Phenotype cascade screening of index subjects and first-degree relatives.
- Clinical diagnosis using Simon Broome criteria.
- Next-generation sequencing for variants in LDLR, APOB, PCSK9, and LDLRAP1 genes.
Main Results:
- Of 700 subjects screened, 479 (68.4%) had probable or definite FH.
- Genetic analysis confirmed FH in 285 of 479 (59.5%) clinically diagnosed individuals.
- 37 subjects (7.7%) had multiple FH-causing variants, including 4 Black African subjects.
Conclusions:
- The Wits FIND-FH program effectively identifies FH cases through cascade screening.
- The program is increasing the identification of FH in Black South Africans.
- A notable proportion of individuals possess multiple FH-associated genetic variants.
Objective:
Due to gene founder effects, familial hypercholesterolemia (FH) has a prevalence of ≈1:80 in populations of Afrikaner ancestry and is a major contributor to premature atherosclerotic cardiovascular disease in South Africans of Jewish and Indian descent. No systematic program exists to identify these families. Furthermore, information regarding FH prevalence in Black Africans is sparse. The Wits FIND-FH program was initiated in late 2016 to address these issues. Approach and Results: Based on index subjects with definite or probable FH, first-degree relatives were contacted, informed consent obtained, and targeted medical history, physical examination, and blood samples collected. In patients with likely FH using the Simon Broome criteria, DNA analysis for LDLR (low-density lipoprotein receptor), APOB (apolipoprotein B), PCSK9 (proprotein convertase subtilisin/kexin type 9), and LDLRAP1 (LDLR adaptor protein 1) variants was analyzed by next-generation sequencing. Of the initial 700 subjects screened of whom 295 (42%) were index cases, 479 (68.4%) were clinically diagnosed with probable or definite FH. Genetic analysis confirmed 285 of 479 (59.5%) as having variants consistent with FH. Three subjects met the clinical diagnosis for homozygous FH, but DNA analysis revealed a further 34 patients, including 4 Black African subjects, with ≥2 FH-causing variants.
Conclusions:
Using phenotype cascade screening, the Wits FIND-FH program has screened an average of 30 subjects monthly of whom 68% had a clinical diagnosis of FH with ≈60% genetically confirmed. The program is identifying a small but growing number of Black South Africans with FH. Interestingly, 37 subjects (7.7%) who underwent DNA testing were found to have ≥2 FH-causing variants.