Double-heterozygous autosomal dominant hypercholesterolemia: Clinical characterization of an underreported disease

Area of Science:

• Genetics
• Cardiovascular Medicine
• Biochemistry

Background:

• Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease (CVD) risk.
• Mutations in LDLR, APOB, and PCSK9 genes are known causes of ADH.

Purpose of the Study:

• To characterize the clinical presentation of individuals with two distinct mutations in ADH-causing genes (double heterozygotes).
• To compare lipid levels and CVD events in double heterozygotes with those in heterozygous, unaffected relatives, and homozygous/compound heterozygous carriers.

Main Methods:

• Identified double heterozygotes (LDLR/APOB or LDLR/PCSK9) from a national DNA diagnostics laboratory database.
• Collected and analyzed clinical data, including lipid profiles and CVD events.
• Compared data from double heterozygotes with familial controls and homozygous/compound heterozygous carriers.

Main Results:

• Twenty-eight double heterozygotes were identified (23 LDLR/APOB, 5 LDLR/PCSK9).
• Off-treatment LDL-C levels in double heterozygotes (8.4 ± 2.8 mmol/L) were significantly higher than in heterozygous (5.6 ± 2.2 mmol/L) and unaffected relatives (2.5 ± 1.1 mmol/L).
• LDL-C levels were significantly lower than in homozygous/compound heterozygous carriers (13.0 ± 5.1 mmol/L).

Conclusions:

• Double-heterozygous carriers exhibit an intermediate clinical phenotype between heterozygous and homozygous/compound heterozygous ADH.
• Accurate molecular identification of double heterozygosity is important for appropriate patient screening and education.
• This understanding aids in distinguishing severe heterozygous ADH from true double heterozygosity.