CFTR function is impaired in a subset of patients with pancreatitis carrying rare CFTR variants.

BACKGROUND: Many affected by pancreatitis harbor rare variants of the cystic fibrosis (CF) gene, CFTR, which encodes an epithelial chloride/bicarbonate channel. We investigated CFTR function and the effect of CFTR modulator drugs in pancreatitis patients carrying CFTR variants. METHODS: Next-generation sequencing was performed to identify CFTR variants. Sweat tests and nasal potential difference (NPD) assays were performed to assess CFTR function in vivo. Intestinal current measurement (ICM) was performed on rectal biopsies. Patient-derived intestinal epithelial monolayers were used to evaluate chloride and bicarbonate transport and the effects of a CFTR modulator combination: elexacaftor, tezacaftor and ivacaftor (ETI). RESULTS: Of 32 pancreatitis patients carrying CFTR variants, three had CF-causing mutations on both alleles and yielded CF-typical sweat test, NPD and ICM results. Fourteen subjects showed a more modest elevation in sweat chloride levels, including three that were provisionally diagnosed with CF. ICM indicated impaired CFTR function in nine out of 17 non-CF subjects tested. This group of nine included five carrying a wild type CFTR allele. In epithelial monolayers, a reduction in CFTR-dependent chloride transport was found in six out of 14 subjects tested, whereas bicarbonate secretion was reduced in only one individual. In epithelial monolayers of four of these six subjects, ETI improved CFTR function. CONCLUSIONS: CFTR function is impaired in a subset of pancreatitis patients carrying CFTR variants. Mutations outside the CFTR locus may contribute to the anion transport defect. Bioassays on patient-derived intestinal tissue and organoids can be used to detect such defects and to assess the effect of CFTR modulators.

Hybrid Shell-Beam Inverse Finite Element Method for the Shape Sensing of Stiffened Thin-Walled Structures: Formulation and Experimental Validation on a Composite Wing-Shaped Panel.

This work presents a novel methodology for the accurate and efficient elastic deformation reconstruction of thin-walled and stiffened structures from discrete strains. It builds on the inverse finite element method (iFEM), a variationally-based shape-sensing approach that reconstructs structural displacements by matching a set of analytical and experimental strains in a least-squares sense. As iFEM employs the finite element framework to discretize the structural domain and as the displacements and strains are approximated using element shape functions, the kind of element used influences the accuracy and efficiency of the iFEM analysis. This problem is addressed in the present work through a novel discretization scheme that combines beam and shell inverse elements to develop an iFEM model of the structure. Such a hybrid discretization paradigm paves the way for more accurate shape-sensing of geometrically complex structures using fewer sensor measurements and lower computational effort than traditional approaches. The hybrid iFEM is experimentally demonstrated in this work for the shape sensing of bending and torsional deformations of a composite stiffened wing panel instrumented with strain rosettes and fiber-optic sensors. The experimental results are accurate, robust, and computationally efficient, demonstrating the potential of this hybrid scheme for developing an efficient digital twin for online structural monitoring and control.

Implantable medical devices for tendon and ligament repair: a review of patents and commercial products.

INTRODUCTION: Tendon and ligament injuries are a frequent and debilitating issue that affects many patients worldwide. The predominant solution is the suture thread, which is not without potential side effects and limitations. Implantable medical devices have gained more attention as an alternative approach. However, due to the many challenges of the inner body environment (limited available space, chemically aggressive environment, etc), the development of suitable devices is not exempt from practical and technical difficulties. AREAS COVERED: Here, implantable medical devices for tendon and ligaments injuries are reviewed and discussed. Commercially-available products and registered patents are all considered as long as they fit the standard definitions of 'implantable medical devices' (reported in the Introduction). The research was then narrowed down to five commercial products, deemed as the most representative of the whole market. Their effectiveness and performance are analysed, as well as the possible areas of improvement and development. EXPERT OPINION: Commercially available products present overall superior mechanical performances than suture techniques. Nevertheless, these latter ones might be still preferred for their wider range of customization. This aspect, and many others, could represent an area of improvement for implantable medical devices, to further explore their potential for tendon and ligament repair.

Design and Mechanical Characterization Using Digital Image Correlation of Soft Tissue-Mimicking Polymers.

Present and future anatomical models for biomedical applications will need bio-mimicking three-dimensional (3D)-printed tissues. These would enable, for example, the evaluation of the quality-performance of novel devices at an intermediate step between ex-vivo and in-vivo trials. Nowadays, PolyJet technology produces anatomical models with varying levels of realism and fidelity to replicate organic tissues. These include anatomical presets set with combinations of multiple materials, transitions, and colors that vary in hardness, flexibility, and density. This study aims to mechanically characterize multi-material specimens designed and fabricated to mimic various bio-inspired hierarchical structures targeted to mimic tendons and ligaments. A Stratasys® J750™ 3D Printer was used, combining the Agilus30™ material at different hardness levels in the bio-mimicking configurations. Then, the mechanical properties of these different options were tested to evaluate their behavior under uni-axial tensile tests. Digital Image Correlation (DIC) was used to accurately quantify the specimens' large strains in a non-contact fashion. A difference in the mechanical properties according to pattern type, proposed hardness combinations, and matrix-to-fiber ratio were evidenced. The specimens V, J1, A1, and C were selected as the best for every type of pattern. Specimens V were chosen as the leading combination since they exhibited the best balance of mechanical properties with the higher values of Modulus of elasticity (2.21 ± 0.17 MPa), maximum strain (1.86 ± 0.05 mm/mm), and tensile strength at break (2.11 ± 0.13 MPa). The approach demonstrates the versatility of PolyJet technology that enables core materials to be tailored based on specific needs. These findings will allow the development of more accurate and realistic computational and 3D printed soft tissue anatomical solutions mimicking something much closer to real tissues.

Non-Destructive Techniques for the Condition and Structural Health Monitoring of Wind Turbines: A Literature Review of the Last 20 Years.

A complete surveillance strategy for wind turbines requires both the condition monitoring (CM) of their mechanical components and the structural health monitoring (SHM) of their load-bearing structural elements (foundations, tower, and blades). Therefore, it spans both the civil and mechanical engineering fields. Several traditional and advanced non-destructive techniques (NDTs) have been proposed for both areas of application throughout the last years. These include visual inspection (VI), acoustic emissions (AEs), ultrasonic testing (UT), infrared thermography (IRT), radiographic testing (RT), electromagnetic testing (ET), oil monitoring, and many other methods. These NDTs can be performed by human personnel, robots, or unmanned aerial vehicles (UAVs); they can also be applied both for isolated wind turbines or systematically for whole onshore or offshore wind farms. These non-destructive approaches have been extensively reviewed here; more than 300 scientific articles, technical reports, and other documents are included in this review, encompassing all the main aspects of these survey strategies. Particular attention was dedicated to the latest developments in the last two decades (2000-2021). Highly influential research works, which received major attention from the scientific community, are highlighted and commented upon. Furthermore, for each strategy, a selection of relevant applications is reported by way of example, including newer and less developed strategies as well.

Effects of the Manufacturing Methods on the Mechanical Properties of a Medical-Grade Copolymer Poly(L-lactide-co-D,L-lactide) and Poly(L-lactide-co-ε-caprolactone) Blend.

Biocompatible and biodegradable polymers represent the future in the manufacturing of medical implantable solutions. As of today, these are generally manufactured with metallic components which cannot be naturally absorbed within the human body. This requires performing an additional surgical procedure to remove the remnants after complete rehabilitation or to leave the devices in situ indefinitely. Nevertheless, the biomaterials used for this purpose must satisfy well-defined mechanical requirements. These are difficult to ascertain at the design phase since they depend not only on their physicochemical properties but also on the specific manufacturing methods used for the target application. Therefore, this research was focused on establishing the effects of the manufacturing methods on both the mechanical properties and the thermal behavior of a medical-grade copolymer blend. Specifically, Injection and Compression Molding were considered. A Poly(L-lactide-co-D,L-lactide)/Poly(L-lactide-co-ε-caprolactone) blend was considered for this investigation, with a ratio of 50/50 (w/w), aimed at the manufacturing of implantable devices for tendon repair. Interesting results were obtained.

A Comparative Analysis of Signal Decomposition Techniques for Structural Health Monitoring on an Experimental Benchmark.

Signal Processing is, arguably, the fundamental enabling technology for vibration-based Structural Health Monitoring (SHM), which includes damage detection and more advanced tasks. However, the investigation of real-life vibration measurements is quite compelling. For a better understanding of its dynamic behaviour, a multi-degree-of-freedom system should be efficiently decomposed into its independent components. However, the target structure may be affected by (damage-related or not) nonlinearities, which appear as noise-like distortions in its vibrational response. This response can be nonstationary as well and thus requires a time-frequency analysis. Adaptive mode decomposition methods are the most apt strategy under these circumstances. Here, a shortlist of three well-established algorithms has been selected for an in-depth analysis. These signal decomposition approaches-namely, the Empirical Mode Decomposition (EMD), the Hilbert Vibration Decomposition (HVD), and the Variational Mode Decomposition (VMD)-are deemed to be the most representative ones because of their extensive use and favourable reception from the research community. The main aspects and properties of these data-adaptive methods, as well as their advantages, limitations, and drawbacks, are discussed and compared. Then, the potentialities of the three algorithms are assessed firstly on a numerical case study and then on a well-known experimental benchmark, including nonlinear cases and nonstationary signals.

3D printing and testing of rose thorns or limpet teeth inspired anchor device for tendon tissue repair.

PURPOSES: Advancements in medical technology have enabled medical specialists to resolve significant problems concerning tendon injuries. However, despite the latest improvements, surgical tendon repair remains challenging. This study aimed to explore the capabilities of the current state-of-the-art technologies for implantable devices. METHODS: After performing extensive patent landscaping and literature review, an anchored tissue fixation device was deemed the most suitable candidate. This design was firstly investigated numerically, realizing a Finite Element Model of the device anchored to two swine tendons stumps, to simulate its application on a severed tendon. Two different hook designs, both bio-inspired, were tested while retaining the same device geometry and anchoring strategy. Then, the applicability of a 3D-printed prototype was tested on swine tendons. Finally, the device-tendon stumps ensemble was subjected to uniaxial tensile tests. RESULTS: The results show that the investigated device enables a better load distribution during the immobilized limb period in comparison to standard suture-based approaches, yet it still presents several design flaws. CONCLUSIONS: The current implantable solutions do not ensure an optimal result in terms of strength recovery. This and other weak points of the currently available proposals will serve as a starting point for future works on bio-inspired implantable devices for tendon repair.

Shape Sensing of Plate Structures Using the Inverse Finite Element Method: Investigation of Efficient Strain-Sensor Patterns.

Methods for real-time reconstruction of structural displacements using measured strain data is an area of active research due to its potential application for Structural Health Monitoring (SHM) and morphing structure control. The inverse Finite Element Method (iFEM) has been shown to be well suited for the full-field reconstruction of displacements, strains, and stresses of structures instrumented with discrete or continuous strain sensors. In practical applications, where the available number of sensors may be limited, the number and sensor positions constitute the key parameters. Understanding changes in the reconstruction quality with respect to sensor position is generally difficult and is the aim of the present work. This paper attempts to supplement the current iFEM modeling knowledge through a rigorous evaluation of several strain-sensor patterns for shape sensing of a rectangular plate. Line plots along various sections of the plate are used to assess the reconstruction quality near and far away from strain sensors, and the nodal displacements are studied as the sensor density increases. The numerical results clearly demonstrate the effectiveness of the strain sensors distributed along the plate boundary for reconstructing relatively simple displacement patterns, and highlight the potential of cross-diagonal strain-sensor patterns to improve the displacement reconstruction of more complex deformation patterns.

Novel Compound Heterozygous Mutations in IL-7 Receptor α Gene in a 15-Month-Old Girl Presenting With Thrombocytopenia, Normal T Cell Count and Maternal Engraftment.

Patients with severe combined immunodeficiency (SCID) exhibit T lymphopenia and profound impairments in cellular and humoral immunity. IL-7 receptor α (IL-7Rα) deficiency is a rare form of SCID that usually presents in the first months of life with severe and opportunistic infections, failure to thrive and high risk of mortality unless treated. Here, we reported an atypical and delayed onset of IL7Rα-SCID in a 15-month-old girl presenting with thrombocytopenia. Immunological investigations showed a normal lymphocyte count with isolated CD4-penia, absence of naïve T cells, marked hypergammaglobulinemia, and maternal T cell engraftment. Targeted next generation sequencing (NGS) revealed two novel compound heterozygous mutations in the IL-7Rα gene: c.160T>C (p.S54P) and c.245G>T (p.C82F). The atypical onset and the unusual immunological phenotype expressed by our patient highlights the diagnostic challenge in the field of primary immunodeficiencies (PID) and in particular in SCID patients where prompt diagnosis and therapy greatly affects survival.

Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and paediatric pulmonary hypertension.

Rare variants in the T-box transcription factor 4 gene (TBX4) have recently been recognised as an emerging cause of paediatric pulmonary hypertension (PH). Their pathophysiology and contribution to persistent pulmonary hypertension in neonates (PPHN) are unknown. We sought to define the spectrum of clinical manifestations and histopathology associated with TBX4 variants in neonates and children with PH.We assessed clinical data and lung tissue in 19 children with PH, including PPHN, carrying TBX4 rare variants identified by next-generation sequencing and copy number variation arrays.Variants included six 17q23 deletions encompassing the entire TBX4 locus and neighbouring genes, and 12 likely damaging mutations. 10 infants presented with neonatal hypoxic respiratory failure and PPHN, and were subsequently discharged home. PH was diagnosed later in infancy or childhood. Three children died and two required lung transplantation. Associated anomalies included patent ductus arteriosus, septal defects, foot anomalies and developmental disability, the latter with a higher prevalence in deletion carriers. Histology in seven infants showed abnormal distal lung development and pulmonary hypertensive remodelling.TBX4 mutations and 17q23 deletions underlie a new form of developmental lung disease manifesting with severe, often biphasic PH at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies.

Using Video Processing for the Full-Field Identification of Backbone Curves in Case of Large Vibrations.

Nonlinear modal analysis is a demanding yet imperative task to rigorously address real-life situations where the dynamics involved clearly exceed the limits of linear approximation. The specific case of geometric nonlinearities, where the effects induced by the second and higher-order terms in the strain-displacement relationship cannot be neglected, is of great significance for structural engineering in most of its fields of application-aerospace, civil construction, mechanical systems, and so on. However, this nonlinear behaviour is strongly affected by even small changes in stiffness or mass, e.g., by applying physically-attached sensors to the structure of interest. Indeed, the sensors placement introduces a certain amount of geometric hardening and mass variation, which becomes relevant for very flexible structures. The effects of mass loading, while highly recognised to be much larger in the nonlinear domain than in its linear counterpart, have seldom been explored experimentally. In this context, the aim of this paper is to perform a noncontact, full-field nonlinear investigation of the very light and very flexible XB-1 air wing prototype aluminum spar, applying the well-known resonance decay method. Video processing in general, and a high-speed, optical target tracking technique in particular, are proposed for this purpose; the methodology can be easily extended to any slender beam-like or plate-like element. Obtained results have been used to describe the first nonlinear normal mode of the spar in both unloaded and sensors-loaded conditions by means of their respective backbone curves. Noticeable changes were encountered between the two conditions when the structure undergoes large-amplitude flexural vibrations.

Trans-heterozygosity for mutations enhances the risk of recurrent/chronic pancreatitis in patients with Cystic Fibrosis.

BACKGROUND: Recurrent (RP) and chronic pancreatitis (CP) may complicate Cystic Fibrosis (CF). It is still unknown if mutations in genes involved in the intrapancreatic activation of trypsin (IPAT) or in the pancreatic secretion pathway (PSP) may enhance the risk for RP/CP in patients with CF. METHODS: We enrolled: 48 patients affected by CF complicated by RP/CP and, as controls 35 patients with CF without pancreatitis and 80 unrelated healthy subjects. We tested a panel of 8 genes involved in the IPAT, i.e. PRSS1, PRSS2, SPINK1, CTRC, CASR, CFTR, CTSB and KRT8 and 23 additional genes implicated in the PSP. RESULTS: We found 14/48 patients (29.2%) with mutations in genes involved in IPAT in the group of CF patients with RP/CP, while mutations in such genes were found in 2/35 (5.7%) patients with CF without pancreatitis and in 3/80 (3.8%) healthy subjects (p < 0.001). Thus, we found mutations in 12 genes of the PSP in 11/48 (22.9%) patients with CF and RP/CP. Overall, 19/48 (39.6%) patients with CF and RP/CP showed one or more mutations in the genes involved in the IPAT and in the PSP while such figure was 4/35 (11.4%) for patients with CF without pancreatitis and 11/80 (13.7%) for healthy controls (p < 0.001). CONCLUSIONS: The trans-heterozygous association between CFTR mutations in genes involved in the pathways of pancreatic enzyme activation and the pancreatic secretion may be risk factors for the development of recurrent or chronic pancreatitis in patients with CF.

Influence of the patellar button thickness on the knee flexion after total knee arthroplasty.

PURPOSE: One of the main problems of knee replacement is the limit of knee flexion. This study focuses on the knee implant and the patellar component currently in use in total knee arthroplasty, analyzing the influence of patellar thickness on the degree of knee flexion following surgery. METHODS: A kinematics study was performed to evaluate whether an optimal patellar thickness can be identified, which enables the maximum flexion angle to be achieved. Using TC images, a healthy model was built. On this basis, a model of a knee joint which had undergone total knee arthroplasty using a Legion PS prosthesis was constructed. Initially, the standard thickness of patellar implant (9 mm) was used to build the model; then several different patellar implant thicknesses (in the range of 5-15 mm) were analyzed. RESULTS: The results show a non-linear trend: a button thickness of less than 9 mm does not change the flexion angle, whereas a button thickness of over 9 mm results in a loss of flexion. The flexion loss is significant in the first two additions of thicknesses but negligible in the last ones. CONCLUSIONS: In the case studied, flexion reduction is not linearly proportional to the patellar thickness. The outcome of total knee arthroplasty is considered to be satisfactory with the standard patellar button. The results of this study could be used to compare the kinematics with other total prosthesis and patellar implants, and should enable the optimization of the patellar residue bone thickness to obtain deep flexion.

Interstitial 10q21.1q23.31 Duplication due to Meiotic Recombination of a Paternal Balanced Complex Rearrangement: Cytogenetic and Molecular Characterization.

Complex chromosomal rearrangements (CCRs) are structural aberrations involving more than 2 chromosomal breakpoints. They are associated with different outcomes depending on the deletion/duplication of genomic material, gene disruption, or position effects. Balanced CCRs can also undergo missegregation during meiotic division, leading to unbalanced derivative chromosomes and, in some cases, to affected offspring. We report on a patient presenting with developmental and speech delay, growth retardation, microcephaly, hypospadias, and dysmorphic features, harboring an interstitial 10q21.1q23.31 duplication, due to recombination of a paternal CCR. Application of several cytogenetic and molecular techniques allowed determining the biological bases of the rearrangement, understanding the underlying chromosomal mechanism, and assessing the reproductive risk.

Novel Dominant Mutation in BIN1 Gene Causing Mild Centronuclear Myopathy Revealed by Myalgias and CK Elevation.

We present the clinical, morphological and molecular data of an Italian family with centronuclear myopathy, carrying a novel pathogenic mutation of BIN1 gene in heterozygous state, consistent with autosomal dominant inheritance. The proband, a 56-years-old man suffered of lower limbs myalgia and slight CK elevation. Clinical examination revealed no muscle weakness, short stature, mild symmetric eyelid ptosis, scapular winging, ankle retraction and well-developed muscles. Muscle biopsy showed nuclear centralization and clustering, deep sarcolemmal invaginations and type 1 fibers hypotrophy. Muscle MRI revealed fatty infiltration of posterior legs compartments, lumbar paraspinal and serratus muscles. By sequencing BIN1, we identified a heterozygous pathogenic mutation [c.107C>A (p.A36E)], and we demonstrate that the mutation strongly impairs the membrane tubulation property of the protein. One affected sister with similar phenotype carried the same mutation. Our findings expand the clinical, morphological and genetic spectrum of the autosomal dominant CNM associated with BIN1 mutations.

Extensive molecular analysis suggested the strong genetic heterogeneity of idiopathic chronic pancreatitis.

Rationale: Genetic features of Chronic Pancreatitis (CP) have been extensively investigated mainly testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. Objectives: 80 patients with Idiopathic CP were investigated using Next Generation Sequencing approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen; modifier genes of Cystic Fibrosis phenotype; pancreatic secretion and ion homeostasis; Calcium signalling and zymogen granules exocytosis; autophagy; autoimmune pancreatitis related genes. Results: We detected mutations in 34 out of 70 genes examined; 64/80 patients (80.0%) were positive for mutations in one or more genes, 16/80 patients (20.0%) had no mutations. Mutations in CFTR were detected in 32/80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38/64 patients positive for mutations showed variants in two or more genes (59.3%). Conclusions: Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in chronic pancreatitis and that trans-heterozygosity may predispose to the idiopathic CP phenotype.

Advantages of a next generation sequencing targeted approach for the molecular diagnosis of retinoblastoma.

BACKGROUND: Retinoblastoma (RB) is the most common malignant childhood tumor of the eye and results from inactivation of both alleles of the RB1 gene. Nowadays RB genetic diagnosis requires classical chromosome investigations, Multiplex Ligation-dependent Probe Amplification analysis (MLPA) and Sanger sequencing. Nevertheless, these techniques show some limitations. We report our experience on a cohort of RB patients using a combined approach of Next-Generation Sequencing (NGS) and RB1 custom array-Comparative Genomic Hybridization (aCGH). METHODS: A total of 65 patients with retinoblastoma were studied: 29 cases of bilateral RB and 36 cases of unilateral RB. All patients were previously tested with conventional cytogenetics and MLPA techniques. Fifty-three samples were then analysed using NGS. Eleven cases were analysed by RB1 custom aCGH. One last case was studied only by classic cytogenetics. Finally, it has been tested, in a lab sensitivity assay, the capability of NGS to detect artificial mosaicism series in previously recognized samples prepared at 3 different mosaicism frequencies: 10, 5, 1 %. RESULTS: Of the 29 cases of bilateral RB, 28 resulted positive (96.5 %) to the genetic investigation: 22 point mutations and 6 genomic rearrangements (four intragenic and two macrodeletion). A novel germline intragenic duplication, from exon18 to exon 23, was identified in a proband with bilateral RB. Of the 36 available cases of unilateral RB, 8 patients resulted positive (22 %) to the genetic investigation: 3 patients showed point mutations while 5 carried large deletion. Finally, we successfully validated, in a lab sensitivity assay, the capability of NGS to accurately measure level of artificial mosaicism down to 1 %. CONCLUSIONS: NGS and RB1-custom aCGH have demonstrated to be an effective combined approach in order to optimize the overall diagnostic procedures of RB. Custom aCGH is able to accurately detect genomic rearrangements allowing the characterization of their extension. NGS is extremely accurate in detecting single nucleotide variants, relatively simple to perform, cost savings and efficient and has confirmed a high sensitivity and accuracy in identifying low levels of artificial mosaicisms.

Relationship between CFTR and CTRC variants and the clinical phenotype in late-onset cystic fibrosis disease with chronic pancreatitis.

Cystic fibrosis (CF), the most common autosomal recessive disease in whites, is caused by mutations in the CF transmembrane conductance regulator (CFTR). So far, >1900 mutations have been described, most of which are nonsense, missense, and frameshift, and can lead to severe phenotypes, reducing the level of function of the CFTR protein. Synonymous variations are usually considered silent without pathogenic effects. However, synonymous mutations exhibiting exon skipping as a consequence of aberrant splicing of pre-mRNA differ. Herein, we describe the effect of the aberrant splicing of the c.273G>C (G91G) synonymous variation found in a 9-year-old white (ΔF508) patient affected by CF and pancreatitis associated with a variant in chymotrypsin C (CTRC). Magnetic resonance imaging showed an atrophic pancreatic gland with substitution of the pancreatic parenchyma with three cysts. Genetic examination revealed compound heterozygosity for the c.1521_1523delCTT (ΔF508) pathogenic variant and the c.273G>C (G91G) variant in CFTR. Sweat test results confirmed the diagnosis of CF. We have thus identified a synonymous variation (G91G) causing the skipping of exon 3 in a CF patient carrying the ΔF508 mutation. However, the clinical phenotype with pancreatic symptoms encouraged us to investigate a panel of pancreas-related genes, which resulted in finding a known sequence variation inside CTRC. We further discuss the role of these variants and their possible interactions in determining the current phenotype.

Telomere shortening and telomere position effect in mild ring 17 syndrome.

BACKGROUND: Ring chromosome 17 syndrome is a rare disease that arises from the breakage and reunion of the short and long arms of chromosome 17. Usually this abnormality results in deletion of genetic material, which explains the clinical features of the syndrome. Moreover, similar phenotypic features have been observed in cases with complete or partial loss of the telomeric repeats and conservation of the euchromatic regions. We studied two different cases of ring 17 syndrome, firstly, to clarify, by analyzing gene expression analysis using real-time qPCR, the role of the telomere absence in relationship with the clinical symptoms, and secondly, to look for a new model of the mechanism of ring chromosome transmission in a rare case of familial mosaicism, through cytomolecular and quantitative fluorescence in-situ hybridization (Q-FISH) investigations. RESULTS: The results for the first case showed that the expression levels of genes selected, which were located close to the p and q ends of chromosome 17, were significantly downregulated in comparison with controls. Moreover, for the second case, we demonstrated that the telomeres were conserved, but were significantly shorter than those of age-matched controls; data from segregation analysis showed that the ring chromosome was transmitted only to the affected subjects of the family. CONCLUSIONS: Subtelomeric gene regulation is responsible for the phenotypic aspects of ring 17 syndrome; telomere shortening influences the phenotypic spectrum of this disease and strongly contributes to the familial transmission of the mosaic ring. Together, these results provide new insights into the genotype-phenotype relationships in mild ring 17 syndrome.