Detection of Familial Hypercholesterolaemia (FH)
Using Next Generation Sequencing (NGS)
Dr Boitumelo Phiri, Dr Carolyn Fedler and Dr Jessica Trusler
Ampath Chat No. 73 (Version 2)
Key Messages
- Genetic testing for FH is available at Ampath using advanced NGS technology.
- The panel includes complete sequencing of three major genes: LDLR, APOB, PCSK9.
- NGS enables detection of:
- Known/founder variants
- Familial variants
- Multiple and novel variants — all in a single test
- Turnaround time: Approximately 4 weeks
Background
Familial hypercholesterolaemia (FH) is the most common autosomal dominant inherited lipid disorder.
Prevalence:
- Global: 1 in 250 to 1 in 500
- South Africa: As high as 1 in 70
- Higher prevalence in:
- Afrikaner
- Ashkenazi Jewish
- Indian populations
- Unknown prevalence in Black South Africans
Caused by pathogenic variants (mutations) that affect the LDL receptor, resulting in high LDL-cholesterol (LDL-C).
Most common gene: LDLR
Other genes: APOB and PCSK9
Clinical Significance
FH leads to chronically elevated LDL-C, causing:
- Atherosclerotic plaques in:
- Skin
- Tendons
- Coronary arteries
- Proximal aorta
- Symptoms:
- Xanthomata
- Arcus corneae
- Early-onset coronary artery disease (CAD)
HeFH – Heterozygous FH
- Common
- Appears in early adulthood
- LDL-C levels are double normal
- High CAD risk:
- 50% in males
- ~30% in females by age 60
HoFH – Homozygous FH
- Very rare
- LDL-C ≥ 13 mmol/L
- Severe xanthomas
- CAD in childhood
- 100× risk of ASCVD if untreated
Diagnostic Guidelines
Several international criteria are used:
- 🇳🇱 Dutch Lipid Clinic criteria
- 🇺🇸 Med Ped criteria
- 🇬🇧 Simon Broome criteria
In South Africa, the Wits FIND-FH programme has shown:
- NGS as a powerful cascade testing tool
- Helps identify FH in Black individuals
- Assists with family member screening
Early diagnosis = early treatment = reduced morbidity and mortality
Testing Protocol Summary (FIND-FH)
Flowchart criteria include:
- Suspected FH
- LDL-C levels ≥4.9 mmol/L
- Clinical markers (xanthomas, arcus ≤45 yrs)
- First-degree relatives with premature CAD
- LDL-C response to therapy
- Follow-up testing of relatives using NGS if index case has an FH mutation
NGS includes variants in LDLR, APOB, PCSK9, LDLRAP1
Contact
For more info or assistance:
Genetics Lab: 012 678 0645
Ask to speak to a clinical genetic counsellor