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Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). Targeted Next Generation Sequencing (NGS) is a new opportunity to expand the existing pathogenic variants (PVs) spectrum associated to FH. Our aim was to report a diagnostic NGS-based approach to detect variants associated to FH. We report two patients: a 48-year-old Asian woman, without known history of hypercholesterolemia and a 46-year-old Caucasian man, with childhood hypercholesterolemia. An effective NGS-based pipeline, FH-Devyser kit/Amplicon Suite, beginning from sequencing to data analysis, did not identify known PVs in the LDLR, APOB, APOE, LDLRAP1, STAP1 and PCSK9 genes, but revealed two novel LDLR variants (c.1564A>T, p.Ile522Phe and c.1688C>T, p.Pro563Leu). This study showed that an effective NGS-based pipeline led to a definitive diagnosis in two FH families, allowing to plan their therapeutic treatment. Although the functional consequence of the two LDLR variants needs to be assessed in vitro, the in silico analysis and high preservation of the two amino acid positions observed in the LDLR protein, across different animal species, suggest that both variants are deleterious.


Simona Moffa, Giorgia Mazzuccato, Maria De Bonis, Elisa De Paolis, Maria Elisabetta Onori, Alfredo Pontecorvi, Andrea Urbani, Andrea Giaccari, Ettore Capoluongo, Angelo Minucci. Identification of two novel LDLR variants by Next Generation Sequencing. Annali dell'Istituto superiore di sanita. 2020 Jan-Mar;56(1):122-127

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PMID: 32242544

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