Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study

Background Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDL-cholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality. Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major candidate genes for monogenic hypercholesterolemia (LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1). Results A total of 213 variants were detected in 1076 subjects. About 90% of them had a pathogenic or likely pathogenic variants. More than 94% of patients carried pathogenic variants in LDLR gene, 27 of which were novel. Pathogenic variants in APOB and PCSK9 were exceedingly rare. We found 4 true homozygotes and 5 putative compound heterozygotes for pathogenic variants in LDLR gene, as well as 5 double heterozygotes for LDLR/APOB pathogenic variants. Two patients were homozygous for pathogenic variants in LDLRAP1 gene resulting in autosomal recessive hypercholesterolemia. One patient was found to be heterozygous for the ApoE variant p.(Leu167del), known to confer an FH phenotype. Conclusions This study shows the molecular characteristics of the FH patients identified in Italy over the last two years. Full phenotypic characterization of these patients and cascade screening of family members is now in progress

Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)

BACKGROUND AND AIMS: Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network). METHODS: Observational, multicenter, retrospective and prospective study involving about 40 Italian clinical centers. Genetic testing of the appropriate candidate genes at one of six molecular diagnostic laboratories serving as nationwide DNA diagnostic centers. RESULTS AND CONCLUSIONS: From 2012 to October 2016, available biochemical and clinical information of 3480 subjects with familial hypercholesterolemia identified according to the Dutch Lipid Clinic Network (DLCN) score were included in the database and genetic analysis was performed in 97.8% of subjects, with a mutation detection rate of 92.0% in patients with DLCN score 656. The establishment of the LIPIGEN network will have important effects on clinical management and it will improve the overall identification and treatment of primary dyslipidemias in Italy

Stability and Structures of Silver Subnanometer Clusters in EMT Zeolite with Maximum Aluminum Content

The stability of small silver clusters, Ag_<i>n</i> with <i>n</i> = 3, 4, 6, and 8, supported in a sodalite of EMT zeolite with a maximum possible aluminum content (Si/Al = 1) was studied with the density-functional-theory-based cluster approach. The results showed that various silver clusters, partially or completely reduced, can be stabilized in this zeolite with the maximum negative defects. Computed formation energies for two reduction reactions reveal that completely reduced Ag clusters can be stabilized through hydrogenation, giving some preference to the formation of hydrogenated Ag₆ species. The hydrogenated neutral Ag_<i>n</i>H_<i>m</i>/EMT clusters remain stable at <i>T</i> = 300 K, as obtained from the analysis of the Born–Oppenheimer molecular dynamics trajectories. Ion exchange of Na⁺ by Ag⁺ cations is obtained to be exothermic with energy gain of 0.5 eV per Ag cation. The formation of Ag–O ionic bonds, known to stabilize metal clusters in zeolitic frameworks, is found to be preponderant in the structures with fewer than six silver atoms, which leads to strong geometrical deformations especially for Ag₃ and Ag₄ species. The largest possibly stabilized in the sodalite completely reduced silver cluster is Ag₈. Partially reduced intact structures are obtained stable for silver clusters with <i>n</i> ≥ 4. Formation energies predict a coexistence of silver exchanged cations and partially reduced silver clusters with several oxidation states in the sodalite. The density of states spectra (DOSS) of the supported completely and partially reduced Ag₄ and Ag₈ clusters are very similar despite the different cluster size, topology, and reduction degrees. DOSS of the host zeolite did not undergo any changes due to the interaction with silver clusters