Identification and Molecular Characterization of a Novel Large-Scale Variant (Exons 4_18 Loss) in the LDLR Gene as a Cause of Familial Hypercholesterolaemia in an Italian Family

Abstract: Next-generation sequencing (NGS) is nowadays commonly used for clinical purposes, and represents an efficient approach for the molecular diagnosis of familial hypercholesterolemia (FH). Although the dominant form of the disease is mostly due to the low-density lipoprotein receptor (LDLR) small-scale pathogenic variants, the copy number variations (CNVs) represent the underlying molecular defects in approximately 10% of FH cases. Here, we reported a novel large deletion in the LDLR gene involving exons 4–18, identified by the bioinformatic analysis of NGS data in an Italian family. A long PCR strategy was employed for the breakpoint region analysis where an insertion of six nucleotides (TTCACT) was found. Two Alu sequences, identified within intron 3 and exon 18, could underlie the identified rearrangement by a nonallelic homologous recombination (NAHR) mechanism. NGS proved to be an effective tool suitable for the identification of CNVs, together with small-scale alterations in the FH-related genes. For this purpose, the use and implementation of this cost-effective, efficient molecular approach meets the clinical need for personalized diagnosis in FH cases

MEDITS-based information on the deep water red shrimps Aristaeomorpha foliacea and Aristeus antennatus (Crustacea: Decapoda: Aristeidae)

Special Volume: Mediterranean marine demersal resources: the Medits international trawl survey (1994-1999)The application of statistical models on a time series of data arising from the MEDITS International Trawl Survey, an experimental demersal resources survey carried out during six years (1994-1999) in the same season of the year (late spring - early summer) using the same fishing gear in a large part of the Mediterranean, has allowed for a study to compare, for the first time, the space-time distribution, abundance, and size structure of the two Aristeids Aristaeomorpha foliacea and Aristeus antennatus throughout most of the Mediterranean Sea. This research has shown a large variability among the six reference areas, that were arbitrarily defined within the basin. In particular the two shrimps do not seem to present any correlation or yield continuity in the years. The same lack of homogeneity was also observed in the time trend of the abundances and frequencies of each of the two species. These data seem to confirm the intrinsic variability of the species, the cause of which is still unknown and undocumented. Nevertheless, a longitudinal gradient of catches has been observed where A. antennatus is more abundant in the west and A. foliacea in the east of the basinVersión del editor1,006

Low-grade gliomas in patients with Noonan syndrome: case-based review of the literature

Noonan syndrome (NS) is a congenital autosomic dominant condition characterized by a variable spectrum from a clinical and genetical point of view. Germline mutations in more than ten genes involved in RAS–MAPK signal pathway have been demonstrated to cause the disease. An higher risk for leukemia and solid malignancies, including brain tumors, is related to NS. A review of the published literature concerning low grade gliomas (LGGs) in NS is presented. We described also a 13-year-old girl with NS associated with a recurrent mutation in PTPN11, who developed three different types of brain tumors, i.e., an optic pathway glioma, a glioneuronal neoplasm of the left temporal lobe and a cerebellar pilocytic astrocytoma. Molecular characterization of the glioneuronal tumor allowed to detect high levels of phosphorylated MTOR (pMTOR); therefore, a therapeutic approach based on an mTOR inhibitor (everolimus) was elected. The treatment was well tolerated and proved to be effective, leading to a stabilization of the tumor, which was surgical removed. The positive outcome of the present case suggests considering this approach for patients with RASopathies and brain tumors with hyperactivated MTOR signaling

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.CAG was supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number P50 HD103525. This work was funded by PID2020-112831GB-I00 AEI /10.13039/501100011033 (MN). SS was supported by a grant from the NIH/NINDS (K23NS119666). SWS is supported by the Hospital for Sick Children Foundation, Autism Speaks, and the University of Toronto McLaughlin Center. EM-G was supported by a grant from MICIU FPU18/06240. EVS. was supported by a grant from the NIH (EY025718). CRF was supported by the fund to support clinical research careers in the Region of Southern Denmark (Region Syddanmarks pulje for kliniske forskerkarriereforløb).Peer reviewe

Multimodal transport Axis Design. Forecast model for crossover solutions in road network reconnection

none3A. Capra; S. Rinelli; G. SpinazzolaA., Capra; Rinelli, Savino; G., Spinazzol

Bean protein isolate supplementation affects the glycemic response to a mediterranean meal

Affiche publicitaire dans les halls de l’aéroport d’Orly Les grandes multinationales ne sont pas les seuls acteurs de la mondialisation. Celle-ci s’incarne aussi dans des formes moins visibles d’échange, qui prennent place dans des espaces souvent tenus pour marginaux. A l’intersection de plusieurs sciences sociales, ce carnet de recherche rend compte de cette autre géographie de la mondialisation, beaucoup plus discrète. Pour sortir de l’ombre ces espaces, il est indispensable de déplacer n..