Unveiling Compound Heterozygous Familial Hypercholesterolemia

Abstract

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis A 38-year-old female with a history of hypercholesterolemia as well as a family history of hypercholesterolemia in mother diagnosed at age 68 and in young daughter at age 11 is referred for further evaluation and management of hypercholesterolemia. Objective/Purpose To review the role of genetic testing in management of severe hypercholesterolemia. Methods In addition to routine clinical care, genetic testing was completed by Invitae using gene sequencing and deletion/duplication analysis with next generation sequencing technology (NGS). Results A 38-year-old female has been treated since age 20, when she was first found to have high cholesterol. She is referred for further evaluation after her 11-year-old daughter is noted to have high cholesterol. Invitae Familial Hypercholesterolemia Panel identified a LDLR: c.1027 G>A (p.Gly343Ser) pathogenic variant and LDLR: c.1880 C>T (p.Ala627Val) variant of uncertain significance (VUS). Conclusions Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease, with a prevalence of 1 in 311, characterized by significantly elevated LDL cholesterol (LDL-C) and responsible for up to 2%-3% of heart attacks in individuals younger than age 60 years. In fact, men with FH who are untreated have a 50% chance of having a coronary event by age 50 and untreated women have a 30% risk by age 60. FH is caused by pathogenic (disease-causing) variants in four major genes: APOB, LDLR, LDLRAP1, PCSK9. The severity of the LDL-C elevation can be determined by the specific variant's impact on LDL-receptor activity and function, and/or the impact from other genes that raise and/or lower the LDL-C. Pathogenic variants in the APOB and PCSK9 and additional LDLR variants may be present as well and are described as double heterozygotes if different genes are affected, compound heterozygotes if different alleles in the same gene are affected, or homozygous if 2 copies of the pathogenic variant is found. In our clinical case, genetic testing revealed a pathogenic variant in the LDLR gene, c.1027 G>A (p.Gly343Ser). This gene is responsible for effective transport of LDL cholesterol into the cell, when defective leads to build up of the un-transported cholesterol in blood vessels. In addition to the pathogenic LDLR variant, a VUS in the LDLR gene, c.1880 C>T (p.Ala627Val) was identified. Variants are of uncertain significance generally do not have evidence to determine pathogenicity with little to no direct impact on phenotype. For now, our patient should be considered heterozygous FH based upon the single pathogenic variant. However, given the supporting evidence and expectation that the VUS is likely pathogenic, we did advise her that the genetic description may change to compound heterozygous depending upon database expansion. Of note, the underrepresentation of this variant in existing databases may reflect sampling bias. Our patient is of Afro-Caribbean (Haitian) heritage, which is a population that has been underrepresented in medical studies. Nothing to disclose.