What is the clinical evidence from this study?

Study design: Observational. Population: Homozygous autosomal dominant hypercholesterolaemia (hoADH) (n=104682). Primary outcome: Prevalence and phenotypical characteristics of molecularly defined hoADH.

What question did this study set out to answer?

This research aims to determine the prevalence and clinical features of homozygous autosomal dominant hypercholesterolaemia (hoADH) in the Netherlands.

April 24, 2026Open Access

Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome

Key Result

The prevalence of molecularly defined hoADH in the Netherlands was estimated at ~1:300,000, with only 50% of patients meeting clinical criteria (LDL-C >13.0 mmol/L).

Key Points

This research aims to determine the prevalence and clinical features of homozygous autosomal dominant hypercholesterolaemia (hoADH) in the Netherlands.
Analyzed data from a nationwide molecular diagnostic center.
Screened 104,682 individuals for molecular defects to identify hoADH cases.
Excluded carriers of non-pathogenic mutations and reviewed medical records for lipid levels and CVD events.
Identified 49 individuals with hoADH, with a prevalence of ∼1 : 300,000.
Mean LDL-C levels were 12.9 ± 5.1 mmol/L prior to treatment.
Only 50% of patients met clinical criteria for hoADH, and 29% experienced a CVD event.

Study Design

Type

Observational (n=104,682)

Multicenter

Yes

Structured PICO

Population

104,682 individuals screened for molecular defects in the Netherlands, identifying 49 patients with molecularly defined homozygous autosomal dominant hypercholesterolaemia (hoADH) (20 true homozygotes, 25 compound heterozygotes for LDLR mutations, 4 homozygous for APOB mutations).

Outcome

Prevalence of molecularly defined hoADH and phenotypical characteristics including lipid levels and cardiovascular disease (CVD) events.

The prevalence of molecularly defined hoADH in the Netherlands is higher (~1:300,000) and the clinical phenotype more variable than previously assumed, highlighting the need for a uniform definition.

Abstract

AIMS: Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD). The exact prevalence of molecularly defined hoADH is unknown. Therefore, we investigated the prevalence and phenotypical characteristics of this disease in an open society, i.e. the Netherlands. METHODS AND RESULTS: The database of the nationwide ADH molecular diagnostic center was queried to identify all molecularly defined hoADH patients. Carriers of non-pathogenic mutations were excluded. Medical records were analysed for data regarding lipid levels and CVD events. Of 104,682 individuals screened for molecular defects, 49 were classified as hoADH (0.05%); 20 were true homozygotes, 25 were compound heterozygotes for LDLR mutations, and 4 were homozygous for APOB mutations. No bi-allelic PCSK9 mutation carriers were identified. Consequently, the prevalence of hoADH was estimated to be ∼1 : 300,000. Mean LDL-C levels prior to lipid-lowering treatment were 12.9 ± 5.1 mmol/L (range 4.4-21.5 mmol/L). Surprisingly, only 50% of the patients met the clinical criteria for hoADH (LDL-C >13.0 mmol/L); 29% of patients suffered from a CVD event. CONCLUSION: The prevalence of molecularly defined hoADH is much higher and the clinical phenotype is more variable than previously assumed. In light of the fact that novel therapies are, or will be registered for the treatment of hoADH patients, an uniform definition of hoADH either as a phenotypic or molecular entity is warranted in order to identify patients who are considered to be eligible for these novel agents.