Table 3 Clinical recommendations on genetic testing and counselling for familial hypercholesterolaemia
Clinical recommendations | Class | Level |
|---|---|---|
1. Genetic testing for FH should be offered to all individuals in whom there is a strong suspicion of FH based on clinical and/or family history (for example, phenotypic HoFH, definite or highly probable phenotypic HeFH in an adult, child or adolescent) | 1 | B |
2. Genetic testing should be considered in individuals with a probable phenotypic diagnosis of HeFH | 2 | B |
3. Genetic testing may be considered in individuals with a phenotypic diagnosis of possible HeFH, especially when there is incomplete information to establish a diagnosis and the genetic result affects clinical management | 3 | C |
4. Genetic testing for FH should be carried out using an accredited method in a certified laboratory, using targeted next-generation sequencing of all exons and exon–intron boundaries of LDLR, APOB, PCSK9 and LDLRAP1, and the exons in APOB that encode the LDLR ligand-binding region, as well as analysis for deletions and duplications in LDLR | 1 | A |
5. Variants detected by genetic testing should be classified and reported according to contemporary standardized guidelines, for example, those of the ACMG, AMP or ClinGen FH Variant Curation Expert Panel | 1 | A |
6. If a pathogenic or likely pathogenic variant is not detected, FH should not be excluded, particularly if the clinical phenotype is strongly suggestive of FH, because the condition may result from undetected genetic variants | 1 | A |
7. Genetic counselling should be offered, before and after genetic testing, to all individuals suspected of having FH | 1 | B |
8. Genetic counselling should at a minimum include obtaining a three-generation family medical history, risk and psychological assessment, family-based care, enabling of cascade testing, anticipatory guidance and psychological assessment | 1 | A |
9. Pre-conception counselling should be offered to all couples, especially if both partners/parents are known, or suspected, to have FH | 1 | B |
10. Prenatal or pre-implantation genetic testing should be offered if both partners/parents are known to have FH, counselling being particularly important in parents with HeFH who have previously had a child with HoFH | 1 | C |
11. Polygenic scores for hypercholesterolaemia may be useful but are not yet fully standardized, so that they should be used with caution when assessing the differential diagnosis of FH in clinical practice | 3 | B |
12. Cascade genetic testing is highly cost-effective and should be used after a disease-causing variant has been identified in the proband or index case | 1 | A |
13. Pre-test and post-test genetic counselling should be offered to all at-risk relatives as an integral component of cascade testing | 1 | A |
14. Cascade testing should be undertaken using both phenotypic and genotypic approaches (Fig. 1); if genetic testing is not available, a phenotypic approach (that is, a plasma or serum lipid profile, including the LDL-cholesterol concentration) should be used | 1 | A |
15. Cascade genetic testing for the specific variant (variants) identified in the proband (that is, known familial variant testing) should initially be offered to all first-degree relatives; if first-degree relatives are unavailable, or do not wish to undergo testing, known familial variant testing should be offered to at-risk second-degree and then third-degree relatives, with sequential extension to the entire family until all at-risk individuals have been offered testing (Fig. 1) | 1 | A |
16. At-risk children should be offered cascade genetic testing at the earliest opportunity (and more than once if not pursued at the first offer) if an FH-causing variant has been identified in a parent or other first-degree relative | 1 | A |
17. When genetic testing is not feasible, the diagnosis of FH in at-risk relatives should be made phenotypically using age-specific, sex-specific and country-specific LDL-cholesterol concentrations (Fig. 1; Supplementary Material 4); clinical tools for diagnosing FH probands (such as the Dutch Lipid Clinic Network criteria and Simon Broome criteria) are not valid for this purpose. Phenotypic cascade testing should initially be offered to all first-degree relatives. If first-degree relatives are unavailable, or decline testing, phenotypic testing should next be offered to second-degree and then third-degree relatives, with sequential extension to the entire family until all at-risk individuals have been offered testing | 1 | A |
18. ‘Reverse’ cascade testing (from child to parents) should be offered to parents after a child is identified as a proband with FH, such as after making a diagnosis following a clinical presentation or via a universal or newborn screening programme | 1 | B |
