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With the regional law n. 26 of December 30, 2020, the Friuli Venezia Giulia Region wanted to promote the establishment of the Regional Register of Sudden Cardiac Death, with the aim of favoring the study of all those deaths that occurred suddenly and unexpectedly under the age of 50 years in which it is not possible to trace the cause of death with certainty. Such dramatic events, difficult to quantify considering the complexity of data collection, are often accepted with resignation without any further investigation of the possible causes. The Regional Register of Sudden Cardiac Deaths of Friuli Venezia Giulia was born from this premise and from the awareness of the importance of going back with a rigorous scientific methodology and through a multidisciplinary approach, to the diagnosis of hereditary heart diseases which, when determined, allow the enrollment of relatives in a cardiological screening process and, therefore, primary prevention of potentially fatal events. The authors describe the operating procedures feeding the Regional Register and present the results of the first year of activity on 26 cases.

Hearing loss (HL), both syndromic (SHL) and non-syndromic (NSHL), is the most common sensory disorder, affecting ~460 million people worldwide. More than 50% of the congenital/childhood cases are attributable to genetic causes, highlighting the importance of genetic testing in this class of disorders. Here we applied a multi-step strategy for the molecular diagnosis of HL in 125 patients, which included: (1) an accurate clinical evaluation, (2) the analysis of GJB2, GJB6, and MT-RNR1 genes, (3) the evaluation STRC-CATSPER2 and OTOA deletions via Multiplex Ligation Probe Amplification (MLPA), (4) Whole Exome Sequencing (WES) in patients negative to steps 2 and 3. Our approach led to the characterization of 50% of the NSHL cases, confirming both the relevant role of the GJB2 (20% of cases) and STRC deletions (6% of cases), and the high genetic heterogeneity of NSHL. Moreover, due to the genetic findings, 4% of apparent NSHL patients have been re-diagnosed as SHL. Finally, WES characterized 86% of SHL patients, supporting the role of already know disease-genes. Overall, our approach proved to be efficient in identifying the molecular cause of HL, providing essential information for the patients' future management.

Hearing loss (HL), one of the most common congenital disorder, affects about one child in 1000. Among the genetic forms of HL, ∼30% of the cases are associated with other signs or symptoms, leading to Syndromic Hearing Loss (SHL) with about 700 different forms described so far. In this report, we refer the clinical and molecular data of 38 Italian SHL unrelated patients, and their relatives, affected by the most common syndromes associated with HL (i.e., Usher, Pendred, Charge, Waardenburg, Alport, Stickler, Branchiootorenal and Microdeletions syndromes). Patients have been analysed using next-generation sequencing (NGS) and High Density (HD)-SNP array technologies. Data analysis led to the identification of nine novel and 27 known causative mutations in 12 genes and two microdeletions in chromosomes 1 and 10, respectively. In particular, as regards to Usher syndrome, that affects 32% of our patients, we were able to reach a molecular diagnosis in 83% of the cases and to identify in Northern Eastern Italy a very common USH2A gene mutation (39%) (c.11864G > A, p.(Trp3955*) which can be defined "Central-Eastern European allele." As regards to Alport syndrome, we were able to potentially reclassify a pathogenic allele in the COL4A3 gene, previously associated only with benign familial hematuria. In all the other cases, the genomic analysis allowed us to confirm the role of known causative genes and to identify several novel and known alleles. Overall, our results highlight the effectiveness of combining an accurate clinical characterization with the use of genomic technologies (NGS and SNP arrays) for the molecular diagnosis of SHL, with a clear positive impact in the management and treatment of all the patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cystic fibrosis (CF) is a common recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. More than 1800 different mutations have been described to date. Here, we report 3 novel mutations in CFTR in 3 Italian CF patients. To detect and identify 36 frequent mutations in Caucasians, we used the INNO-LiPA CFTR19 and INNO-LiPA CFTR17+Tn Update kits (Innogenetics; Ghent, Belgium). Our first analysis did not reveal both of the responsible mutations; thus, direct sequencing of the CFTR gene coding region was performed. The 3 patients were compound heterozygous. In one allele, the F508del (c.1521_1523delCTT, p.PHE508del) mutation in exon 11 was observed in each case. For the second allele, in patient No.1, direct sequencing revealed an 11-base pair deletion (GAGGCGATACT) in exon 14 (c.2236_2246del; pGlu746Alafs*29). In patient No. 2, direct sequencing revealed a nonsense mutation at nucleotide 3892 (c.3892G>T) in exon 24. In patient No. 3, direct sequencing revealed a deletion of cytosine in exon 27 (c.4296delC; p.Asn1432Lysfs*16). These 3 novel mutations indicate the production of a truncated protein, which consequently results in a non-functional polypeptide.

Celiac disease (CD) is a T-cell-mediated chronic inflammatory disease characterized by autoimmune, immunological and environmental components, where genetic factors in addition to the main known risk factors (gliadin and human leukocyte antigen (HLA)-DQ haplotypes) are supposed to be involved. CD14 is a multifunctional receptor involved in the bacterial lipopolysaccharides-dependent signal transduction. The CD14 gene maps on the long arm of chromosome 5 (5q22-q32), a 'hotbed' region for CD; promoter polymorphisms are known to influence its expression. In this study we analyzed three CD14 promoter polymorphisms (c.-1359G>T, c.-1145A>G and c.-159C>T, ) in 938 CD Italian patients and 533 healthy controls, with known HLA-DQ haplotypes, with the aim of evaluating their possible association with the disease. The c.-1145A>G G and c.-159C>T T alleles (as well as the combination of the two alleles in the GT haplotype), were identified as susceptibility factors for CD development, being significantly more frequent in CD patients than in healthy controls. This association was also confirmed when the analysis was restricted to only those subjects characterized by HLA-DQ risk haplotypes. Our results indicate the involvement of CD14 gene polymorphisms in the susceptibility to CD.