Hereditary breast cancer accounts for 5–10% of all cases, with pathogenic variants in BRCA1/2 and other susceptibility genes playing a crucial role. This study elucidates the prevalence and spectrum of germline variants in 13 cancer predisposition genes among high—risk hereditary breast cancer patients from Southern Italy. We employed next-generation sequencing (NGS) to analyze 254 individuals selected through genetic counseling. Pathogenic or likely pathogenic variants were identified in 13% (34/254) of patients, with 54% of these variants occurring in non-BRCA1/2 genes. Notably, we observed a recurrent BRCA1 c.4964_4982del founder mutation, underscoring the importance of population-specific genetic screening. The spectrum of variants extended beyond BRCA1/2 to include PALB2, ATM, TP53, CHEK2, and RAD51C, highlighting the genetic heterogeneity of breast cancer susceptibility. Variants of uncertain significance were detected in 20% of patients, emphasizing the ongoing challenge of variant interpretation in the era of multi-gene panel testing. These findings not only enhance our understanding of the genetic landscape of breast cancer in Southern Italy but also provide a foundation for developing more targeted, population-specific approaches to genetic testing and counseling, ultimately contributing to the advancement of precision medicine in oncology.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventually death. The pathogenesis of ALS is influenced by genetic factors, environmental factors, and age-related dysfunctions. These factors, taken together, are responsible for sporadic cases of ALS, which account for approximately 85–90% of ALS cases, while familial ALS accounts for the remaining 10–15% of cases, usually with dominant traits. Despite advances in understanding and studying the disease, the cause of the onset of ALS remains unknown. Emerging evidence suggests that non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play crucial roles in the pathogenesis of the disease. An abnormal expression of these molecules is implicated in various ALS-related processes, including motor neuron survival, protein aggregation, and inflammation. Here, we describe the dysregulation of non-coding RNAs in the pathogenic mechanism of ALS, highlighting the potential roles of miRNAs, lncRNAs, and circRNAs as biomarkers or therapeutic targets to examine the progression of the disease.

Background: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder caused by homozygosity or compound heterozygosity for pathogenic mutations in the TTR gene, leading to destabilization of the transthyretin tetramer, misfolding of monomers, and subsequent amyloid fibril deposition. Among over 150 known TTR variants, p.Val142Ile is particularly associated with late-onset cardiac involvement and is the most prevalent amyloidogenic mutation in individuals of African and, to a lesser extent, European descent. This study reports the identification and familial segregation of the p.Val142Ile mutation in a large multigenerational family from Calabria (Southern Italy). Methods: Genomic DNA was extracted from peripheral blood, and Sanger sequencing of the TTR gene was performed in the proband and extended family. Results: The proband was a 75-year-old man with clinical features suggestive of cardiac amyloidosis. Genetic testing revealed homozygosity for the TTR p.Val142Ile variant. Family screening revealed multiple heterozygous carriers across three generations, most of whom were asymptomatic. Discussion: This is the first report of a native Calabrian family carrying this variant, previously unreported in this region, where p.Phe84Leu was considered the only endemic TTR mutation. Our findings expand the mutational landscape of ATTRv in Southern Italy and highlight the presence of p.Val142Ile in a previously unrecognized geographic area. These results reinforce the importance of including TTR sequencing in the work-up of unexplained cardiomyopathy, particularly in Southern Italy, where atypical variants may be emerging.

Background: The national guidelines, informed by evidence from the National Institutes of Health (NIH), define the criteria for genetic testing of BRCA1/2 and other genes associated with Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS). When a germline pathogenic variant (PV) is identified in an index case, clinical recommendations advise informing at-risk relatives about the availability of predictive genetic testing, as early identification of carriers allows for timely implementation of preventive measures. Methods: This retrospective observational study examined data collected between 2017 and 2024 at the Medical Genetics Unit of the “Renato Dulbecco” University Hospital in Catanzaro, Italy. The analysis focused on trends in the identification of individuals carrying PVs in cancer predisposition genes (CPGs) and the subsequent uptake of cascade genetic testing (CGT) among their family members. Results: Over the study period, from 116 probands were performed 257 CGTs on 251 relatives. A notable reduction of approximately ten years in median age was observed, 39% were found to carry familial mutation and were referred to personalized cancer prevention programs. Among these, 62% accessed Oncological Genetic Counselling (CGO) within one year of the proband’s diagnosis, suggesting effective communication and outreach. Conclusions: The findings highlight the critical role of effective CGO and intrafamilial communication in hereditary cancer prevention. The identification of PVs, followed by timely CGTs and implementation of preventive strategies, significantly contributes to early cancer risk management. Periodic monitoring of CGT uptake and outcome trends, as demonstrated in this study, is essential to refine and optimize genetic services and public health strategies.

Background/Objectives: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder of mitochondrial fatty acid β-oxidation caused by pathogenic variants in ACADVL. The clinical spectrum is highly heterogeneous, ranging from lethal neonatal cardiomyopathy to late-onset myopathy. This study aims to characterize the rare c.215C>T (p.Ser72Phe) variant, identified in compound heterozygosity with the common pathogenic allele c.848T>C (p.Val283Ala) in a male neonate detected by newborn screening (NBS). Methods: Genetic analysis was performed using Sanger sequencing on the proband and his family members. The pathogenicity of the p.Ser72Phe variant was evaluated through multiple bioinformatic predictors and interpreted according to ACMG/AMP guidelines. To understand the functional impact on the protein, structural modeling was conducted using FoldX 4.0 for energy calculations and UCSF ChimeraX for the visualization of conformational changes and cofactor-binding site perturbations in the VLCAD homodimer. Results: At the end of the first postnatal week, liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis of dried blood spots of the proband revealed a markedly abnormal acylcarnitine profile, with C14:1 levels (1.837 μmol/L) approximately five times above the reference range. Clinical reports documented hypoketotic hypoglycemia, consistent with VLCADD. Segregation analysis demonstrated transmission of both variants within the family, with additional heterozygous and homozygous carriers identified. Bioinformatic predictions uniformly classified p.Ser72Phe as deleterious. This variant has an extremely low allele frequency and affects a highly conserved residue in the FAD-binding domain. Structural modeling with FoldX yielded a mean ΔΔG of +22.63 ± 5.48 kcal/mol, indicating a significant localized thermodynamic burden. Inspection of the mutant model in ChimeraX showed perturbation of the side-chain orientation and attenuation of the local hydrogen-bonding network at the FAD-binding site, together with increased steric packing around residue 72. Taken together, the clinical, genetic, and structural evidence support reclassification of p. Ser72Phe as likely pathogenic according to ACMG criteria, specifically applying the ClinGen ACADVL VCEP specifications. Conclusions: This study expands the ACADVL mutational spectrum and underscores the value of integrating sequencing, segregation, and structural bioinformatics in interpreting rare variants detected through NBS.