Homozygous familial hypercholesterolemia in a high-consanguinity population: Insights from a Saudi cohort

Homozygous familial hypercholesterolemia (HoFH) is a genetic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and a significantly increased risk of early-onset cardiovascular disease (CVD) and premature death. This study investigates the clinical features, treatment outcomes, genetic findings, and reverse cascade screening results for HoFH patients.

A total of 88 HoFH patients from 65 families following at a large referral center between 2010 and 2023 were included. Clinical, genetic, and outcome data were obtained through electronic chart review and phone interviews.

Among the 88 patients (45.4% males; median age: 17 years), LDLR mutations were identified in 100%. Positive family history and consanguinity were reported in 87.5% and 75% of patients, respectively. Reverse cascade screening led to the identification of 76 additional affected relatives, with a median of 7 individuals per family. Treatment included lifestyle modification, lipid-lowering medications (79.5%), LDL apheresis (29.6%), and liver transplantation (20.5%). As for treatment outcomes, liver transplant showed the most significant LDL-C reduction (83.3% decrease, p < .001), followed by lomitapide-based therapy (69.4%, p = .004). Complications included xanthomas (62.5%) and CVD (38.6%), with a mortality rate of 13.6% (median age at death: 16 years), primarily due to cardiovascular events.

HoFH poses an underrecognized public health challenge in Saudi Arabia, particularly in the context of high consanguinity and founder mutations. Early diagnosis through genetic and reverse cascade screening, along with aggressive management, is essential to improving survival. These findings highlight the urgent need for national screening programs and expanded access to advanced lipid-lowering therapies.