Publicação
From Uncertainty To Diagnosis: Functional Reclassification Of LDLR Variants In Familial Hypercholesterolemia
| datacite.subject.fos | Ciências Médicas | |
| dc.contributor.author | Chora, Joana Rita | |
| dc.contributor.author | Islam, Mohammad Majharul | |
| dc.contributor.author | Alves, Ana Catarina | |
| dc.contributor.author | Pfisterer, Simon | |
| dc.contributor.author | Bourbon, Mafalda | |
| dc.date.accessioned | 2026-03-04T12:54:41Z | |
| dc.date.available | 2026-03-04T12:54:41Z | |
| dc.date.issued | 2025-10-31 | |
| dc.description.abstract | Objectives: Familial hypercholesterolaemia (FH) is a common disorder of lipid metabolism marked by an increased risk of premature atherosclerotic cardiovascular disease. While genetic testing confirms diagnosis, many LDLR variants are classified as variants of uncertain significance (VUS) due to lack of evidence, limiting clinical actionability. Functional assays can support reclassification, but conventional approaches are time-consuming. This study aims to use a high-throughput functional pipeline to evaluate LDLR VUS and improve diagnostic precision in FH. Methods: We analysed 133 LDLR VUS lacking functional evidence using an automated analysis platform based on multiplexed high-content imaging to quantify LDL uptake. Variants were classified based on uptake relative to wild-type: <70% for PS3_Supporting (pathogenic) and >90% for BS3_Supporting (benign), according to LDLR-specific ACMG/AMP guidelines. A subset of 46 “hot VUS” required only one supporting criterion to reach a likely benign or likely pathogenic classification. Results: Of the 133 variants, 53 showed <70% uptake and were assigned PS3_Supporting, while 41 showed >90% uptake and received BS3_Supporting. The remaining 39 variants exhibited intermediate activity (70–90%). Among the 46 hot VUS, 12 were reclassified as likely benign and 11 as likely pathogenic. An additional 43 variants are now one supporting criterion away from potential reclassification. Conclusions: High-throughput functional testing provides robust and rapid evidence for LDLR variant interpretation. By adding evidence about LDLR activity these assays contribute to resolve diagnostic uncertainty and enables earlier and more accurate diagnosis, optimizes cascade screening, and enables better risk stratification to inform treatment options. These findings support a shift toward personalised genomic medicine in lipid disorders, with direct implications for patient care and cardiovascular risk reduction. | eng |
| dc.description.sponsorship | PerMedFH project funded by La Caixa Foundation in partnership with FCT. JR Chora is funded by the PerMedFH project (LCF/PR/HP23/52330032. | |
| dc.identifier.uri | http://hdl.handle.net/10400.18/11112 | |
| dc.language.iso | eng | |
| dc.peerreviewed | n/a | |
| dc.relation | LCF/PR/HP23/52330032 | |
| dc.rights.uri | N/A | |
| dc.subject | Familial Hypercholesterolemia | |
| dc.subject | Variant Classification | |
| dc.subject | Functional Studies | |
| dc.subject | Genetic Diagnosis | |
| dc.subject | Doenças Cardio e Cérebro-vasculares | |
| dc.title | From Uncertainty To Diagnosis: Functional Reclassification Of LDLR Variants In Familial Hypercholesterolemia | eng |
| dc.type | conference object | |
| dspace.entity.type | Publication | |
| oaire.citation.conferenceDate | 2025 | |
| oaire.citation.conferencePlace | Figueira da Foz, Portugal | |
| oaire.citation.title | XXXIII Congresso Português de Aterosclerose, 31 outubro-1 novembro 2025 | |
| oaire.version | http://purl.org/coar/version/c_b1a7d7d4d402bcce |