Management implications of results of positive genetic testing for LDLR, APOB, and PCSK9

Management implications of results of positive genetic testing for LDLR, APOB, and PCSK9

Children

Hyperlipidemia expertise should be sought.
Thorough family history, physical examination, and lipid profile.
Cardiology should evaluate those with homozygous FH to assess cardiac function and provide other interventions as appropriate.
Statin therapy for elevated LDL-C.*
- Initiated as early as infancy for homozygous FH.
- Initiated as early as age 8 to 10 years for heterozygous FH.
Additional lipid-lowering approaches are almost invariably required for those with homozygous FH.
Counseling and testing of at-risk relatives.^¶

Adults

Thorough family history, physical examination, and lipid profile.
Thorough cardiovascular risk assessment.
Statin therapy for elevated LDL-C.*
- High-intensity statin for most heterozygous FH.
- Other approaches may be appropriate for those with homozygous FH (LDL-apheresis, lomitapide, a PCSK9 inhibitor).
Attention to other cardiovascular risk reduction strategies (avoidance of smoking, screening and management of diabetes and hypertension, management of diet and weight).
Counseling and testing of at-risk relatives.^¶

Positive genetic testing refers to a finding of one or more pathogenic or likely pathogenic variants. Management is mostly the same regardless of which gene(s) are involved. For those with a variant of uncertain significance (VUS), management is based on family history and assessment of the tested individual (cardiovascular disease and/or cardiovascular risk factors, including lipid profile). Management decisions should involve shared decision-making with the tested individual and/or their caregivers, especially related to the testing of minor children. Any individual with a positive family history of atherosclerotic disease (cardiovascular, cerebrovascular, or peripheral vascular) should have an evaluation of risk factors including a lipid profile.

LDLR: low-density lipoprotein receptor gene; APOB: apolipoprotein B gene; PCSK9: proprotein convertase subtilisin kexin 9 gene; LDL-C: low-density lipoprotein cholesterol.

* Refer to UpToDate for discussions of target LDL-C, which depends on whether there is preexisting atherosclerotic disease and other cardiovascular risk factors.

¶ Typically refers to first-degree relatives, with cascade testing of their first-degree relatives if they carry a pathogenic or likely pathogenic variant, but in some cases second-degree relatives may be tested directly if first-degree relatives are unavailable for testing.

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Management implications of results of positive genetic testing for LDLR, APOB, and PCSK9