First LDLRAP1 and Recurrent LDLR Mutations in Tunisian Families With Familial Hypercholesterolemia

Area of Science:

• Genetics
• Cardiovascular Disease
• Biochemistry

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL-cholesterol and premature cardiovascular disease.
• Autosomal dominant FH (ADH) involves LDLR, APOB, or PCSK9 variants, while rare autosomal recessive FH (ARH) stems from LDLRAP1 mutations.
• Tunisia has a high consanguinity rate, yet LDLRAP1 variants were previously unreported.

Purpose of the Study:

• To investigate the genetic basis of FH in two consanguineous Tunisian families.
• To identify novel pathogenic variants and understand their functional impact.
• To explore the genetic heterogeneity of FH and its clinical manifestations in the Tunisian population.

Main Methods:

• Whole Exome Sequencing (WES) was performed on two Tunisian families.
• In silico analyses (MutationTaster, DynaMut2, etc.) predicted the functional impact of identified variants.
• ACMG guidelines were used for variant classification.
• Targeted analysis of valvulogenesis genes was conducted.

Main Results:

• Family FH-A showed a recurrent LDLR splice-site variant (c.1845+1G>A) with autosomal dominant inheritance.
• Family FH-B revealed a novel homozygous LDLRAP1 missense variant (c.161G>A; p.Gly54Asp), confirming autosomal recessive inheritance.
• The LDLRAP1 p.Gly54Asp variant likely destabilizes the protein, impairing LDL receptor internalization.
• ARH patients presented with xanthomas and a quadricuspid aortic valve (QAV), with no co-segregating defects in known valvulogenesis genes.
• Phenotypic variability was observed in ADH families with the same LDLR mutation.

Conclusions:

• This study reports the first evidence of LDLRAP1-associated ARH in Tunisia.
• It highlights the genetic heterogeneity of FH and the importance of WES in consanguineous populations.
• The findings underscore the need for integrated molecular, structural, and functional analyses for FH diagnosis and management.
• The QAV in ARH patients may result from embryonic LDL accumulation impacting Notch1 signaling rather than a monogenic defect.