Telethon Institute Of Genetics And Medicine

Core myopathies are congenital diseases with clinical, pathological and genetic heterogeneity. Main histological features are fiber "cores" showing a focally reduced oxidative enzyme activity. Dusty Core Disease (DuCD) differs from Central Core Myopathy for the presence of irregular areas, without clear borders and round/ovoidal shape, and myofibrillar disorganization characterized by reddish purple granular material depositions. This disorder is defined clinically by severe phenotypes with early onset of disease and molecularly by low level of RyR1 in muscle. Until now DuCD was associated only to biallelic recessive RYR1 mutations. We analyzed the clinical aspects, pathological features and mutational spectrum of four DuCD patients, belonging to our cohort of Congenital Myopathy probands. Molecular analysis detected 5 different RYR1 pathogenic variants, two of them so far unreported. Patients presented a heterogeneous phenotype ranging from severe recessive infantile forms to moderate dominant adult-onset presentations. Histological, immunological and ultrastructural techniques were employed to validate these dominant cases, which expand our knowledge on the inheritance of this subgroup of diseases.

X-inactivation is the process of dosage compensation to balance X-linked gene expression levels between females (XX) and males (XY). One of the 2 X-chromosomes is randomly selected for inactivation in each cell during embryogenesis and remains inactive throughout life. Therefore, females have 2 types of cells: those with paternal X-chromosome activation and those with maternal X-chromosome activation. However, it remains unclear how X-inactivation is involved in palate and tooth development. Ofd1 is located on the X-chromosome. We found cleft palate in all heterozygous Ofd1 mutant mice (Ofd1fl/WT;Wnt1Cre[HET]), even though some cells should activate the normal X-chromosome due to random X-inactivation. Cells with Ofd1 mutant X chromosome activation (Ofd1 mutant cells) accumulated at the tip of the palatal shelves due to cell segregation caused by a lack of EFNB1 expression, resulting in a cleft palate in all Ofd1fl/WT;Wnt1Cre(HET) mice. Unlike the palate, Ofd1fl/WT;Wnt1Cre(HET) mice showed multiple tooth phenotypes, including extra and absent incisors, while a normal number of incisors was also found. Accumulation of Ofd1 mutant cells also occurred in the tooth mesenchyme, and these clusters of Ofd1 mutant cells failed to initiate incisor tooth formation due to a lack of Wnt signaling. In contrast to palate development, the location of Ofd1 mutant cell clusters differed between Ofd1fl/WT;Wnt1Cre(HET) mice, likely leading to diversity of tooth phenotypes. Thus, X-inactivation exhibits different involvement between palate and tooth development.

BackgroundPeople with Cystic Fibrosis (pwCF) are prone to bacterial lung infections with P. aeruginosa, which have been linked to chronic inflammation in the lung. Although the highly effective CFTR modulator therapy (Elexacaftor-Tezacaftor-Ivacaftor, ETI) has dramatically improved respiratory outcomes in pwCF, airway inflammation and bacterial colonization persist in the upper and lower respiratory tracts.MethodsWe investigated the effect of ETI in both plasma and fresh primary nasal epithelial (HNE) cells obtained from pwCF pre- and post-three months of ETI treatment. Given that inflammation has been shown to upregulate NFKBIZ and the ATP12A proton pump, we measured their levels in fresh HNE cells and in cultured HNE cells exposed to clinical exoproducts (EXO) of P. aeruginosa or other inflammatory stimuli.ResultsELISA analysis revealed a significant reduction of IL-6, IL-8, and IL-17C in both plasma and HNE cells after ETI treatment. NFKBIZ and ATP12A expression was increased after infection and inflammatory stimuli in CF bronchial epithelial (CFBE) and HNE cells, and this increase was reduced by Dimethyl-Fumarate, an anti-inflammatory drug.ConclusionsThese preclinical studies, using patient-derived tissues, suggest that NFKBIZ and ATP12A may play a relevant role in the pathophysiology and inflammatory response of the CF airway epithelium.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00011-026-02210-z.

Accurate vessel detection and timely information extraction from optical remote sensing imagery are essential for a wide range of maritime surveillance operations, both civilian and defense-related. These include vessel tracking, unauthorized fishing, illegal migration monitoring, and search and rescue missions. Although artificial intelligence (AI) is a key component for achieving reliable and accurate detection in satellite imagery, traditional AI-based remote sensing methodologies rely on ground-based image processing. This dependence leads to significant delays between data acquisition and the generation of actionable insights, which may hinder rapid decision-making during critical maritime situations such as sea disasters. To address this challenge, we propose a novel hardware design based on the Microchip PolarFire System-on-Chip for low-power, real-time vessel detection onboard spacecraft. Our design integrates the FPGA-based CoreVectorBlox engine to accelerate the inference process of SR-YOLOv5s—an enhanced object detection framework built upon YOLOv5s. This detector incorporates a single image super-resolution backbone that allows the extraction of fine details and features of small targets of interest, thus improving detection performance. Experimental results demonstrate that SR-YOLOv5s consistently outperforms the baseline YOLOv5s framework in vessel detection. The model provides high accuracy in detecting very small targets (area ≤ 7 × 7 pixels), achieving a mAP50 of 0.4658 compared to 0.2832—an absolute improvement of 18.26 percentage points. When deployed on the PolarFire FPGA, the end-to-end pipeline sustains real-time operation with an inference latency of 55 ms per frame and an average dynamic power consumption below 1.2 W. These results confirm the suitability of our approach for power-constrained onboard processing and demonstrate its effectiveness as a solution for low-latency alert generation in maritime surveillance through edge-based analysis of Earth observation imagery. • Onboard processing enables low-latency insights for time–critical maritime operations. • Super-resolution boosts object detection in optical remote sensing imagery. • Low-power, rad-tolerant FPGA AI engine for deep learning onboard spacecraft.

Clinical variability in COVID-19 is partly explained by host genetic factors, including inborn errors of immunity. We investigated a patient with a heterozygous nonsense mutation in the TLR3 gene (p.Trp769*) by generating human-induced pluripotent stem cells (hiPSCs) and differentiating them into lung organoids (hLORGs). TLR3-mutated hLORGs showed reduced basal expression of TLR3 and downstream signaling genes. Following infection with a pseudotyped SARS-CoV-2 virus and live SARS-CoV-2, RNA-Seq and qPCR analyses revealed significant upregulation of fibrinogen genes (FGA, FGG), which are associated with severe COVID-19. Interestingly, TLR3 expression remained inducible upon infection, despite the loss-of-function mutation. Our patient-derived hLORG model recapitulates the pathophysiological features of the patient and provides a platform to investigate host-virus interactions and test targeted therapies for genetically at-risk individuals.

Background: Cardiomyopathies are a heterogeneous group of heart muscle disorders with diverse genetic origins. Biallelic loss-of-function (LoF) variants in the nebulin-related anchoring protein (NRAP) gene have been linked to dilated cardiomyopathy (DCM) and left ventricular noncompaction cardiomyopathy, though only a few families have been described. NRAP, a member of the Nebulin family, plays a key role in cardiomyocyte development, structural integrity, and muscle function. Methods: We investigated two Italian siblings with DCM born to consanguineous parents from a small village in Campania. Exome sequencing, homozygosity mapping, and comparative analyses with other reported cases were performed. Genealogical research was conducted using civil registry data to reconstruct extended family pedigrees. Results: Both siblings were homozygous for a LoF variant in NRAP (NM_198060.4:c.619del; p.Val207TrpfsTer20). A third brother with tachycardia-induced cardiomyopathy, as well as their living mother, who did not have cardiac abnormalities, were found to be heterozygous. The same homozygous variant was recently identified in another Italian family with DCM coming from North-eastern Italy, whose proband also originated from a nearby village in Campania. These two families exhibited heterogeneity in clinical presentation. Homozygosity analysis revealed a >25 Mb shared region on chromosome 10 encompassing NRAP, supporting a common ancestral origin. While genealogical reconstruction did not allow identification of a shared ancestor, it confirmed consanguinity and enabled the recognition of potential carriers across both families. Conclusions: Our findings strengthen the evidence for NRAP as a disease-causing gene in cardiomyopathies and highlight a likely founder effect in Campania. Incorporating NRAP into genetic testing panels is warranted, especially in populations with high rates of consanguinity or suspected founder variants.

To describe the genetic, phenotypic, and pathologic manifestations of patients presenting with inherited kidney cancer and germline variants of the Tuberous Sclerosis Complex (TSC) genes. Inherited kidney cancer patients were screened for germline RCC susceptibility gene variants and patient histories and clinical evaluations were performed. Renal tumors were evaluated for somatic genetic alterations by DNA sequencing and mRNA expression analysis by RNAseq and immunohistochemical analyses were performed. Nine distinct germline TSC1/TSC2 variants were identified in 13 patients, including seven known or likely pathogenic alterations. Five patients presented with a clinical diagnosis of TSC, and eleven patients had a genetic diagnosis of TSC. Nine patients had bilateral RCC and nine had multifocal RCC. The average initial age at diagnosis of RCC was 47years old. The TSC-associated tumors demonstrated a variety of histologies including ccRCC, RCC with clear cell and papillary features, chromophobe RCC, and oncocytoma; with ccRCC being the most prevalent. Loss of heterozygosity or secondary somatic alteration of TSC1/TSC2 was observed in ~ 37% of tumors. RNAseq analysis demonstrated specific expression patterns associated within histologically defined tumor clusters and increased expression of CLEAR genes activated by the TFE3/TFEB transcription factors, including GPNMB and NPC1 which were confirmed with immunohistochemistry. This study confirms the importance of screening individuals with a family history of kidney cancer for TSC1/TSC2 germline variants, even in the absence of canonical TSC manifestations, and indicates a critical role of TFE3 and TFEB as drivers of human TSC-deficient renal cell carcinoma.

Skeletal muscles, which constitute 40–50% of body mass, regulate whole-body energy expenditure and glucose and lipid metabolism. Peroxisomes are dynamic organelles that play a crucial role in lipid metabolism and clearance of reactive oxygen species, however their role in skeletal muscle remains poorly understood. To clarify this issue, we generated a muscle-specific transgenic mouse line with peroxisome import deficiency through the deletion of peroxisomal biogenesis factor 5 (Pex5). Here, we show that Pex5 inhibition results in impaired lipid metabolism, reduced muscle force and exercise performance. Moreover, mitochondrial structure, content, and function are also altered, accelerating the onset of age-related structural defects, neuromuscular junction degeneration, and muscle atrophy. Consistent with these observations, we observe a decline in peroxisomal content in the muscles of control mice undergoing natural aging. Altogether, our findings show the importance of preserving peroxisomal function and their interplay with mitochondria to maintain muscle health during aging.

AimTo investigate clinical and molecular features of neurofibromatosis type 1 (NF1)-associated breast cancer (BC) in a large multicenter cohort.MethodsClinical and histopathological data from 86 NF1 patients with BC (69 with molecular data) were collected, and 111 published cases were reviewed. NF1 variants were assessed in silico, and their distribution across neurofibromin domains was compared with the general NF1 population.ResultsNF1 patients developed BC earlier than the general population (mean 49 years), with missense variant heterozygotes showing the earliest onset (43.9 vs. 49.5 years for truncating variants, p = 0.014). Tumors were frequently high-grade (49 %), HER2-enriched (31 %) or luminal B subtypes (31 %), with reduced luminal A (28 %) frequency. NF1+BC patients had more subcutaneous (p = 0.006) and plexiform neurofibromas (p < 0.00001). Compared with the general NF1 population, they lacked large deletions (0 % vs. 3 %, p = 0.0148), showed enrichment for N-HEAT missense variants (70 % vs. 42 %; p = 0.0078), and carried recurrent variants significantly enriched in NF1+BC. Structural modeling predicted deleterious effects for >70 % of variants, with proline/arginine substitutions accounting for 83 % of missense variants (vs. 44 % in the general NF1 population, p = 0.0012).ConclusionsNF1-associated BC is characterized by earlier onset, aggressive tumor features, and distinct mutational patterns.

The Applicability Domain (AD) is a critical element in ensuring the reliability of in silico models for chemical safety assessment, as it defines the space within which model predictions can be considered valid. Despite its relevance, AD is often implemented using generic strategies that fail to account for the specific characteristics of the model and data set, limiting both scientific robustness and regulatory confidence. To address this limitation, we conducted a systematic benchmarking of established AD methods across regression models trained on OECD-compliant data sets, which demonstrated robust predictive ability outperforming established QSAR methods such as read-across. A regulatory-accepted approach demonstrated some limitations; additionally, its rigid structure reliant on fixed parameters and proprietary libraries limited its adaptability and transparency. We therefore reimplemented and optimized it using open-source tools to enhance flexibility, reproducibility, and predictive accuracy. Most notably, our method was demonstrated to be the preferred choice for the highest number of end points. Nonetheless, our analysis highlighted that no single strategy performs best across all scenarios. Driven by these findings and the recognized need for model-adaptive AD assessment, we developed ADvisor, a modular and broadly applicable tool that allows users to evaluate, compare, and implement AD strategies suited to the characteristics of their specific models and data sets, thereby promoting transparency and regulatory compliance in in silico applications.