Hyperlipidaemia

The hereditary hyperlipidaemias differ markedly in severity and organ involvement across the panel. In , lifelong elevation of low-density lipoprotein cholesterol (LDL-C) drives atherosclerotic plaque deposition in the coronary and other arterial beds from an early age, conferring a markedly increased risk of coronary artery disease (CAD). The severe early-onset form of FH presents in childhood with tendon and interdigital xanthomas and aortic stenosis. Defects of the lipoprotein-lipase pathway instead cause severe fasting hypertriglyceridaemia with chylomicronaemia and a high rate of recurrent acute pancreatitis. Lysosomal acid lipase deficiency (LALD) ranges from fatal infantile Wolman disease to milder, later-onset cholesteryl ester storage disease with hepatosplenomegaly and raised liver enzymes. Hepatic triglyceride lipase deficiency is characterised by markedly elevated triglyceride and cholesterol levels with triglyceride-rich lipoproteins and may be associated with premature atherosclerosis and CAD. Some patients also develop xanthomas or corneal arcus, although clinical presentation is variable. APOE-related disorders are characterised by impaired lipoprotein metabolism resulting in dyslipidaemia with elevated cholesterol and/or triglyceride levels.

The estimated prevalence for FH is at least 1/250. This figure reflects the common form of FH, the most frequent entity on the panel; the rare severe childhood-onset form of FH has a prevalence ranging from 1/100,000 up to 1/1,000000. The estimated prevalence for familial chylomicronemia syndrome is 1/300,000, and up to 30 times higher in Quebec, Canada due to founder effects. The prevalence for hepatic triglyceride lipase deficiency is unknown.

This panel analyses genes underlying inherited disorders of lipoprotein metabolism. FH results from impaired clearance of LDL cholesterol, caused by germline loss-of-function variants in LDLR (the most common cause), variants in APOB that impair receptor binding, gain-of-function variants in PCSK9, or biallelic LDLRAP1 variants. Severe hypertriglyceridaemia and the chylomicronaemia syndromes arise from defective lipoprotein-lipase-mediated triglyceride hydrolysis, involving LPL and its cofactors APOC2, APOA5, LMF1 and GPIHBP1. The remaining genes, including APOE, LIPA, and LIPC, underlie familial dysbetalipoproteinaemia, lysosomal acid lipase deficiency and hepatic triglyceride lipase deficiency.

Inheritance varies across the panel. FH due to LDLR, APOB or PCSK9 variants is autosomal dominant, giving first-degree relatives a 50% chance of inheriting the pathogenic variant; LDLRAP1-related hypercholesterolaemia, the chylomicronaemia disorders, lysosomal acid lipase deficiency and hepatic triglyceride lipase deficiency are autosomal recessive. Familial dysbetalipoproteinaemia is typically autosomal recessive, arising from APOE ε2/ε2 homozygosity, though rare dominant forms occur. Rarely, parental germline mosaicism underlies recurrence when both parents are clinically unaffected.

Diagnosis is based on characteristic biochemical findings that differ by disorder. FH is suggested by markedly elevated LDL-C (untreated adults > 190 mg/dl, total cholesterol > 310 mg/dl), lipoprotein lipase disorders by severe fasting hypertriglyceridaemia with chylomicronaemia (triglycerides frequently > 2,000 mg/dl) and lysosomal acid lipase deficiency by reduced enzyme activity. Molecular genetic testing establishes and subclassifies the diagnosis.

Main differential diagnoses include:

• : xanthomas and early coronary disease with haemolytic anaemia and thrombocytopenia; ABCG5, ABCG8
• Familial dysbetalipoproteinaemia: tuberous xanthomas and premature coronary artery disease with raised triglycerides; APOE
• Cerebrotendinous xanthomatosis: xanthomas with normal LDL-C, dementia, ataxia and cataracts; CYP27A1
• Lysosomal acid lipase deficiency: raised LDL-C with hepatosplenomegaly and liver disease; LIPA
• Secondary hypercholesterolaemia: comparable lipid findings from hypothyroidism, diabetes or kidney disease, without a germline variant

and others (six differentials in total).

• Establishing the diagnosis: a molecular genetic result confirms the clinical diagnosis and defines the specific underlying disorder.
• Identification of the germline pathogenic variant supports condition-specific monitoring and management decisions made by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variant is known, at-risk relatives can be offered predictive (cascade) testing to clarify their variant status.

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