Double trouble: Pathogenic LDLR and SCARB1 variants in the same family

Abstract

Background and Aims : LDLR and SCARB1 are the key membrane receptors LDL and HDL. Mutations in the LDLR and SCARB1 genes are identified in 80% of patients with familial hypercholesterolemia and in <<< 1% of patients with hyperalphalipoproteinemia. Mutations in the both genes act co-dominantly, heterozygous carriers demonstrate intermediate levels of LDL-C or HDL-C between wild-type and homozygous individuals. Here we describe a family with extremely high levels of lipoproteins (above the 90th percentile for age and sex) with a rare variant in one or both genes.Methods: NGS was performed by Ion S5 system. Variant validation was performed by PCR-direct sequencing.Results: The proband was admitted to the cardiology department with recurrent fainting and elevated LDL-C levels. We identified two pathogenic variants in a heterozygous state – LDLR(NM_000527.5):c.986G>A (p.Cys329Tyr) (HGMD - CM981186) and SCARB1(NM_005505.5):c.727-2A>C (rs201068540, according to the ACMG criteria the variant is pathogenic). We then determined that sibling is also the carrier of both mutations, the mother has only the SCARB1 variant, the father has only the LDLR variant. Segregation of variants correlates with the lipid profile of patients. The mutation in the SCARB1 gene correlates with a high HDL-C phenotype, and the LDLR mutation with a high LDL-C phenotype.Conclusions: Our findings suggest mutations in the SCARB1 gene are a rare but recurring cause of elevated HDL-C levels. The finding of the combined variants in LDLR/SCARB1 genes triggering hypercholesterolemia and hyperalphalipoproteinemia phenotypes is essential to elaborate the spectrum of variants causing dyslipidemia and to understand the genotype-phenotype correlation. Background and Aims : LDLR and SCARB1 are the key membrane receptors LDL and HDL. Mutations in the LDLR and SCARB1 genes are identified in 80% of patients with familial hypercholesterolemia and in <<< 1% of patients with hyperalphalipoproteinemia. Mutations in the both genes act co-dominantly, heterozygous carriers demonstrate intermediate levels of LDL-C or HDL-C between wild-type and homozygous individuals. Here we describe a family with extremely high levels of lipoproteins (above the 90th percentile for age and sex) with a rare variant in one or both genes. Methods: NGS was performed by Ion S5 system. Variant validation was performed by PCR-direct sequencing. Results: The proband was admitted to the cardiology department with recurrent fainting and elevated LDL-C levels. We identified two pathogenic variants in a heterozygous state – LDLR(NM_000527.5):c.986G>A (p.Cys329Tyr) (HGMD - CM981186) and SCARB1(NM_005505.5):c.727-2A>C (rs201068540, according to the ACMG criteria the variant is pathogenic). We then determined that sibling is also the carrier of both mutations, the mother has only the SCARB1 variant, the father has only the LDLR variant. Segregation of variants correlates with the lipid profile of patients. The mutation in the SCARB1 gene correlates with a high HDL-C phenotype, and the LDLR mutation with a high LDL-C phenotype. Conclusions: Our findings suggest mutations in the SCARB1 gene are a rare but recurring cause of elevated HDL-C levels. The finding of the combined variants in LDLR/SCARB1 genes triggering hypercholesterolemia and hyperalphalipoproteinemia phenotypes is essential to elaborate the spectrum of variants causing dyslipidemia and to understand the genotype-phenotype correlation.