Percorrer por autor "Islam, Mohammad Majharul"
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- The Functional Landscape Of Coding Variation In The Familial Hypercholesterolemia Gene LDLRPublication . Tabet, Daniel R.; Coté, Atina G.; Lancaster, Megan C.; Weile, Jochen; Rayhan, Ashyad; Fotiadou, Iosifina; Kishore, Nishka; Li, Roujia; Kuang, Da; Knapp, Jennifer J.; Carrero, Carmela Serio; Taverniti, Olivia; Axakova, Anna; Castelli, Jack M. P.; Islam, Mohammad Majharul; Sowlati-Hashjin, Shahin; Gandhi, Aanshi; Maaieh, Ranim; Garton, Michael; Matreyek, Kenneth; Fowler, Douglas M.; Bourbon, Mafalda; Pfisterer, Simon G.; Glazer, Andrew M.; Kroncke, Brett M.; Parikh, Victoria N.; Ashley, Euan A.; Knowles, Joshua W.; Claussnitzer, Melina; Cirulli, Elizabeth T.; Hegele, Robert A.; Roden, Dan M.; MacRae, Calum A.; Roth, Frederick P.Variants in the familial hypercholesterolemia gene -the most important genetic driver of cardiovascular disease-can raise circulating low-density lipoprotein (LDL) cholesterol concentrations and increase the risk of premature atherosclerosis. Definitive classifications are lacking for nearly half of clinically encountered missense variants, limiting interventions that reduce disease burden. Here, we tested the impact of ~17,000 (nearly all possible) missense coding variants on both LDLR cell-surface abundance and LDL uptake, yielding sequence-function maps that recapitulate known biochemistry, offer functional insights, and provide evidence for interpreting clinical variants. Functional scores correlated with hyperlipidemia phenotypes in prospective human cohorts and augmented polygenic scores to improve risk inference, highlighting the potential of this resource to accelerate familial hypercholesterolemia diagnosis and improve patient outcomes.
- Re-classification of LDLR Variants through High-Throughput Functional Characterisation: Advancing Diagnosis in Familial HypercholesterolaemiaPublication . Chora, Joana Rita; Islam, Mohammad Majharul; Alves, Ana Catarina; Pfisterer, Simon; Bourbon, MafaldaBackground: 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.