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Re-classification of LDLR Variants through High-Throughput Functional Characterisation: Advancing Diagnosis in Familial Hypercholesterolaemia

2025-12-05Documento de conferência Acesso restrito
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datacite.subject.fosCiências Médicas
dc.contributor.authorChora, Joana Rita
dc.contributor.authorIslam, Mohammad Majharul
dc.contributor.authorAlves, Ana Catarina
dc.contributor.authorPfisterer, Simon
dc.contributor.authorBourbon, Mafalda
dc.date.accessioned2026-02-13T12:38:38Z
dc.date.available2026-02-13T12:38:38Z
dc.date.issued2025-12-05
dc.description.abstractBackground: Familial hypercholesterolaemia (FH) is the most common autosomal disorder of lipid metabolism, affecting approximately 1 in 300 individuals. FH is characterised by markedly elevated plasma cholesterol levels from birth, predisposing to premature atherosclerotic cardiovascular disease. The identification of a pathogenic variant in a causative gene provides a definitive diagnosis and enables cascade screening of family members. However, a substantial proportion of FH variants remain classified as variants of uncertain significance (VUS), creating a critical gap in genetic diagnosis and patient management. Purpose: This study aims to implement a high-throughput pipeline for the functional classification of LDLR variants, thereby enabling their clinical re-interpretation and integration into diagnostic practice. Methods: Selected LDLR variants were divided into two groups: a validation set and a test set. The validation group included 7 variants previously classified as benign/likely benign and 50 variants previously classified as pathogenic/likely pathogenic. The test group comprised 131 VUS with no prior functional assessment. Functional activity was evaluated using an automated analysis platform based on multiplexed high-content imaging to quantify LDL uptake, as described previously (Islam, Tamlander, Hlushchenko, Ripatti, & Pfisterer, 2024). Variant classification followed FH VCEP LDLR-specific guidelines (Chora et al., 2022). Results: In total, 187 LDLR variants were analysed. In the validation group, 44 variants demonstrated completely concordant results with previous classifications, 8 fell within an intermediate "grey zone" (70–90% LDL uptake), and only 5 pathogenic variants were misclassified, yielding a sensitivity of 88.4%, specificity and precision of 100%, and overall accuracy of 78.9%. Among the test group, 51 variants exhibited <70% of wild-type LDL uptake, 41 showed >90% of wild-type uptake, and 39 fell into the intermediate range, requiring additional functional studies. Integrating these findings with other ACMG/AMP evidence codes, 47 variants were considered “hot VUS”, amenable to reclassification. Of these, 9 were reclassified as likely benign and 11 as likely pathogenic. Conclusions: This large-scale functional study of LDLR variants demonstrates the feasibility and clinical utility of integrating high-throughput functional evidence with high accuracy into variant interpretation. The ability to reclassify previously unresolved VUS represents a major step forward in reducing diagnostic uncertainty in FH. The PerMedFH project paves the way for a personalised medicine approach in FH, improving diagnostic precision, and ultimately enhancing patient care and cardiovascular outcomes.eng
dc.description.sponsorshipPerMedFH project funded by La Caixa Foundation in partnership with FCT. JR Chora is funded by the PerMedFH project (LCF/PR/HP23/52330032)
dc.identifier.urihttp://hdl.handle.net/10400.18/10934
dc.language.isoeng
dc.peerreviewedn/a
dc.rights.uriN/A
dc.subjectFamilial Hypercholesterolaemia
dc.subjectGenetic Diagnosis
dc.subjectVariant Classification
dc.subjectFunctional Studies
dc.subjectDoenças Cardio e Cérebro-vasculares
dc.titleRe-classification of LDLR Variants through High-Throughput Functional Characterisation: Advancing Diagnosis in Familial Hypercholesterolaemiaeng
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferenceDate2025-12
oaire.citation.conferencePlaceLisbon, Portugal
oaire.citation.titleESC Cardio Genomics 2025 Conference, 5-6 December 2025
oaire.versionhttp://purl.org/coar/version/c_b1a7d7d4d402bcce

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