Familial hypomagnesaemia, Hypercalciuria and Nephrocalcinosis associated with a novel mutation of the highly conserved leucine residue 116 of Claudin 16 in a Chinese patient with a delayed diagnosis: A case report

Background: Sixty mutations of claudin 16 coding gene have been reported in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) patients. Recent investigations revealed that a highly conserved glycine-leucine-tryptophan (115G-L-W117) motif in the first extracellular segment (ESC1) of claudin 16 might be essential for stabilization of the appropriately folded ECS1 structure and conservation of normal claudin 16 function. However, neither missense nor nonsense mutation has ever been described in this motif. Our study aimed at identifying mutations in a Chinese patient with FHHNC and exploring the association between genotype and phenotype. Case presentation: A 33-year-old female presented with 4 years history of recurrent acute pyelonephritis without other notable past medical history. Her healthy parents, who aged 56 and 53 respectively, were second cousins, and her only sibling died from renal failure without definite cause at age 25. Renal ultrasound imaging demonstrated atrophic kidneys and bilateral nephrocalcinosis. The laboratory workup revealed impaired renal function (Stage CKD IV), hypocalcemia and mild hypomagnesemia, accompanied with marked renal loss of magnesium and hypercalciuria. During the follow-up, treatment with calcitriol and calcium but not with magnesium was difficult to achieve normal serum calcium levels, whereas her serum magnesium concentration fluctuated within normal ranges. In the end, the patient unavoidably reached ESRD at 36 years old. The clinical features and family history suggested the diagnosis of FHHNC. To make a definite diagnosis, we use whole-exome sequencing to identify the disease-causing mutations and Sanger sequencing to confirm the mutation co-segregation in the family. As a result, a novel homozygous mutation (c.346C > G, p.Leu116Val) in115G-L-W117motif of claudin 16 was identified. Her parents, grandmother and one of her cousins carried heterozygous p.Leu116Val, whereas 200 unrelated controls did not carry this mutation. Conclusions: We described a delayed diagnosis patient with FHHNC in the Chinese population and identified a novel missense mutation in the highly conserved115G-L-W117motif of claudin 16 for the first time. According to the reported data and the information deduced from 3D modeling, we speculate that this mutation probably reserve partial residual function which might be related to the slight phenotype of the patient

Identification of a novel TSC2 c.3610G > A, p.G1204R mutation contribute to aberrant splicing in a patient with classical tuberous sclerosis complex: a case report

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in any organ systems. Mutations in the TSC1 or TSC2 gene lead to the dysfunction of hamartin or tuberin proteins, which cause tuberous sclerosis complex. Case presentation: We describe the clinical characteristics of patients from a Chinese family with tuberous sclerosis complex and analyze the functional consequences of their causal genetic mutations. A novel heterozygous mutation (c.3610G > A) at the last nucleotide of exon 29 in TSC2 was identified. On the protein level, this variant was presumed to be a missense mutation (p.Gly1204Arg). However, the splicing assay revealed that this mutation also leads to the whole TSC2 exon 29 skipping, besides the wild-type transcript. The mutated transcript results in an in-frame deletion of 71 amino acids (p.Gly1133_Thr1203del) and its ratio with the normal splice product is of about 44:56. Conclusions: The novel c.3610G > A TSC2 mutation was identified in association with tuberous sclerosis complex. And it was proven to code both for a missense-carrying transcript (56%), and for an isoform lacking exon 29 (44%)

Advanced Ultrasonic Non-destructive Evaluation for Metrological Analysis and Quality Assessment of Impact Damaged Non-crimp Fabric Composites☆

Abstract Composite materials are nowadays massively utilized in a very large number of industrial applications. Thus, it has become essential to characterize the service behaviour they can provide depending on their working conditions. In this paper, the study of the influence of impact conditions on damage generation in high performance composite materials, consisting of non-crimp fabric composite laminates, is carried out through the application of an advanced ultrasonic non-destructive evaluation technique, known as full volume ultrasonic scanning. This technique is based on the pulse-echo immersion testing method and allows for the quantitative analysis of the internal material structure in the entire composite volume. The aim of the ultrasonic non-destructive evaluation analysis is the metrological characterization of the non-crimp fabric composite laminates in terms of actual thickness estimation and stacking sequence fiber orientation verification as well as their quality assessment in terms of impact damage development within the whole composite material volume

Advanced 3D Ultrasonic Non-destructive Evaluation Technique for CFRP aeronautical applications

Nowadays, carbon fiber reinforced plastic (CFRP) composite materials are massively used in a very large number of aeronautical applications such the construction of light weight aircrafts. In aeronautical field, the ultrasonic (UT) non-destructive evaluation NDE technique is are largely used for materials inspection and part quality control because it permits to examine aircraft structures without disassembling them. Damages can occur, at several scales, within this composite material (e.g. delamination) without an external indication. Consequently, each produced composite structure needs to be inspected in order to evaluate the presence of possible defects and to prevent a catastrophic failure of the airplane. In this thesis work an advanced UT NDE system was utilized to perform a reliable and repeatable UT Full Volume (FV) scanning based on pulse-echo immersion testing on three different CFRP aeronautical components that represent three case studies. The resulting ultrasonic data were processed by a custom made software, developed in Labview environment, in order to obtain a metrological characterization and a quality assessment of non-crimp fabric composite laminates (first case study) and by a second custom made software, developed in Matlab environment, in order to provide a 3D thickness reconstruction of the defects of a CFRP bonded joint laminates and of a CFRP drilled laminates (second and the third case respectively)

A 22-Week-Old Fetus with Nager Syndrome and Congenital Diaphragmatic Hernia due to a Novel SF3B4 Mutation.

Nager syndrome, or acrofacial dysostosis type 1 (AFD1), is a rare multiple malformation syndrome characterized by hypoplasia of first and second branchial arches derivatives and appendicular anomalies with variable involvement of the radial/axial ray. In 2012, AFD1 has been associated with dominant mutations in SF3B4. We report a 22-week-old fetus with AFD1 associated with diaphragmatic hernia due to a previously unreported SF3B4 mutation (c.35-2A>G). Defective diaphragmatic development is a rare manifestation in AFD1 as it is described in only 2 previous cases, with molecular confirmation in 1 of them. Our molecular finding adds a novel pathogenic splicing variant to the SF3B4 mutational spectrum and contributes to defining its prenatal/fetal phenotype

Innovazioni tecnologiche per lo studio della complessità del genoma umano

INNOVAZIONI TECNOLOGICHE PER LO STUDIO DELLA COMPLESSITA' DEL GENOMA UMAN

Ultrasonic evaluation of induction heat treatment applied to thermoplastic matrix CFRP

Abstract Thermoplastic matrix carbon fibre reinforced polymers (CFRP) are extensively utilized for composites structures in the aerospace and aeronautical industries. Diverse techniques were currently applied to joining composite parts, the most promising method is the induction heat treatment. In this paper, experimental tests were performed on thermoplastic matrix CFRP specimens by varying the induction heat treatment parameters: power, frequency and current. An advanced ultrasonic (UT) non-destructive evaluation based on pulse-echo technique was employed for the investigation of the utilized process parameters through the UT evaluation of the process induced damage and its depth along the thickness of the thermoplastic matrix CFRP laminates

Integration of reverse engineering and ultrasonic non-contact testing procedures for quality assessment of CFRP aeronautical components

Abstract Nowadays, the quality assurance of aeronautical components is a very crucial issue. Diverse defects can be generated during composite material components manufacturing such as voids, delamination, cracks, etc. The identification of these defects requires the use of different types of inspection methods. In this paper, two diverse non-contact inspection techniques, i.e. a laser-based reverse engineering method and an ultrasonic testing procedure, are integrated to provide a complete quality assessment of carbon fibre reinforced polymer components for applications in the aeronautical field. A custom made software code was developed in order to create a user interface allowing for the visualization and analysis of the reverse engineering and ultrasonic information for the detection of geometrical and internal flaws of the component under inspection

Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic modifier factors and new sequencing technologies are redefining the understanding of genotype–phenotype relationships, even if the interpretations of the numerous identified variants pose several challenges. Methods and results: We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in 3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for the prediction, annotation and visualization of functional variants. Genotype–phenotype correlations were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The 80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants. Conclusions: Our results extend the mutational spectrum of HCM and contribute in defining the molecular pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in a clinical context

Non-contact Reverse Engineering Modeling for Additive Manufacturing of Down Scaled Cultural Artefacts

Abstract In recent years, reverse engineering has achieved a relevant role in the cultural heritage field. The availability of 3D digital models of artefacts opens the door to a new era of cultural heritage: virtual museum creation, artefact cataloguing, conservation, planning and simulation of restoration, monitoring of artefacts subjected to environmental degradation, virtual reconstruction of damaged or missing parts, reproduction of replicas, etc. In this paper, two different non-contact reverse engineering scanning systems were utilized for 3D data acquisition of a cultural heritage artefact. The digital data acquisition and processing procedures of the scanned geometry have been illustrated and compared to evaluate the performance of both systems in terms of data acquisition time, processing time, reconstruction precision and final model quality. Finally, additive manufacturing technologies were applied to reconstruct a down scaled copy of the artefact