Table 2.

Familial Hypercholesterolemia: Phenotype Correlations by Gene

GeneMOIPhenotype 1
APOB ADCan be assoc w/↓ LDL-C levels & less severe presentation than LDLR-related HeFH
ARRare, w/few persons reported. Presentation is reported to be more similar to LDLR-related HeFH, & less severe than LDLR-related HoFH (e.g., ↓ LDL-C levels, later onset of CAD).
LDLR AD↑ LDL-C often >190 mg/dL, ↑ risk of premature CAD; physical exam findings (e.g., xanthomas) may develop over time.
AR
  • Untreated adults often have LDL-C levels >500 mg/dL (>13 mmol/L). In addition to xanthelasmas & tendonous xanthomas, interdigital xanthomas (between fingers) can also occur & develop in childhood. Most persons develop severe CAD by their mid-20s. The rate of either death or coronary bypass surgery by teen years is high [Raal & Santos 2012]. Severe aortic stenosis is also common [Raal & Santos 2012, Raal et al 2016a, Raal et al 2016b].
  • Statins are often relatively ineffective because their efficacy largely depends on upregulation of functional LDL receptors in liver [Raal & Santos 2012]; thus, therapy often requires LDL apheresis in addition to use of multiple other medications, some of which are specifically approved for HoFH, incl PCSK9 inhibitors, lomitapide, & evinacumab (see Management, Treatment of Manifestations).
LDLRAP1 ARPresentation similar to LDLR-related HoFH incl LDL-C >500 mg/dL, early-onset CAD, & aortic valve stenosis. Planar, tuberous, or tendon xanthomas have also been reported to develop in childhood. Persons have had variable response to lipid-lowering therapies, often requiring >1 &/or requiring LDL apheresis. 2
PCSK9 AD
  • Can be assoc w/↓ LDL-C levels & less severe presentation than LDLR-related HeFH
  • Severe, early-onset FH has been reported in a few persons w/whole-gene duplication [Iacocca et al 2018].
ARRare, w/few persons reported. Presentation reported to be more similar to that of LDLR-related HeFH & less severe than LDLR-related HoFH (e.g., ↓ LDL-C levels, later onset of CAD).

AD = autosomal dominant; AR = autosomal recessive; CAD = coronary artery disease; FH = familial hypercholesterolemia; HeFH = heterozygous familial hypercholesterolemia; HoFH = familial hypercholesterolemia due to biallelic (homozygous or compound heterozygous) pathogenic variants in APOB, LDLR, or PCSK9; LDL-C = low-density lipoprotein cholesterol; MOI = mode of inheritance

1.
2.

Data on LDLRAP1 variants is still relatively limited and may evolve over time.

From: Familial Hypercholesterolemia

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