The hospital Israelita Albert Einstein standards for constitutional sequence variants classification: version 2023.

BACKGROUND: Next-generation sequencing has had a significant impact on genetic disease diagnosis, but the interpretation of the vast amount of genomic data it generates can be challenging. To address this, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology have established guidelines for standardized variant interpretation. In this manuscript, we present the updated Hospital Israelita Albert Einstein Standards for Constitutional Sequence Variants Classification, incorporating modifications from leading genetics societies and the ClinGen initiative. RESULTS: First, we standardized the scientific publications, documents, and other reliable sources for this document to ensure an evidence-based approach. Next, we defined the databases that would provide variant information for the classification process, established the terminology for molecular findings, set standards for disease-gene associations, and determined the nomenclature for classification criteria. Subsequently, we defined the general rules for variant classification and the Bayesian statistical reasoning principles to enhance this process. We also defined bioinformatics standards for automated classification. Our workgroup adhered to gene-specific rules and workflows curated by the ClinGen Variant Curation Expert Panels whenever available. Additionally, a distinct set of specifications for criteria modulation was created for cancer genes, recognizing their unique characteristics. CONCLUSIONS: The development of an internal consensus and standards for constitutional sequence variant classification, specifically adapted to the Brazilian population, further contributes to the continuous refinement of variant classification practices. The aim of these efforts from the workgroup is to enhance the reliability and uniformity of variant classification.

A Sol-Gel/Solvothermal Synthetic Approach to Titania Nanoparticles for Raman Thermometry.

The accurate determination of the local temperature is one of the most important challenges in the field of nanotechnology and nanomedicine. For this purpose, different techniques and materials have been extensively studied in order to identify both the best-performing materials and the techniques with greatest sensitivity. In this study, the Raman technique was exploited for the determination of the local temperature as a non-contact technique and titania nanoparticles (NPs) were tested as nanothermometer Raman active material. Biocompatible titania NPs were synthesized following a combination of sol-gel and solvothermal green synthesis approaches, with the aim of obtaining pure anatase samples. In particular, the optimization of three different synthesis protocols allowed materials to be obtained with well-defined crystallite dimensions and good control over the final morphology and dispersibility. TiO2 powders were characterized by X-ray diffraction (XRD) analyses and room-temperature Raman measurements, to confirm that the synthesized samples were single-phase anatase titania, and using SEM measurements, which clearly showed the nanometric dimension of the NPs. Stokes and anti-Stokes Raman measurements were collected, with the excitation laser at 514.5 nm (CW Ar/Kr ion laser), in the temperature range of 293-323 K, a range of interest for biological applications. The power of the laser was carefully chosen in order to avoid possible heating due to the laser irradiation. The data support the possibility of evaluating the local temperature and show that TiO2 NPs possess high sensitivity and low uncertainty in the range of a few degrees as a Raman nanothermometer material.

Genomic study of nonsyndromic hearing loss in unaffected individuals: Frequency of pathogenic and likely pathogenic variants in a Brazilian cohort of 2,097 genomes.

Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy-Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4-15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.

An Apparently Balanced Complex Chromosome Rearrangement Involving Seven Breaks and Four Chromosomes in a Healthy Female and Segregation/Recombination in Her Affected Son.

Duplication of the distal 1q and 4p segments are both characterized by the presence of intellectual disability/neurodevelopmental delay and dysmorphisms. Here, we describe a male with a complex chromosome rearrangement (CCR) presenting with overlapping clinical findings between these 2 syndromes. In order to better characterize this CCR, classical karyotyping, FISH, and chromosomal microarray analysis were performed on material from the patient and his parents, which revealed an unbalanced karyotype with duplications at 1q41q43 and 4p15.2p14 in the proband. The rearrangements, which were derived from a maternal balanced karyotype, included an insertion of a segment from the long to the short arm of chromosome 1, a balanced translocation involving chromosomes 14 and 18, and an insertion of a segment from the short arm of chromosome 4 into the derived chromosome 14. This study aimed to better define the clinical history and prognosis of a patient with this rare category of chromosomal aberration. Our results suggest that the frequency of CCR in the general population may be underestimated; when balanced, they may not have a phenotypic effect. Moreover, they emphasize the need for cytogenetic techniques complementary to chromosomal microarray for proper genetic counseling.

Schmid metaphyseal chondrodysplasia: an example of radiology guidance to molecular diagnosis.

Schmid metaphyseal chondrodysplasia is a rare genetic cause of skeletal dysplasia. Patients usually present skeletal abnormalities but no major visceral malformations or intellectual disability. We report a case of a 2-year-old male patient with short stature, progressive genu varum, and waddling gait. Radiographic findings were essential to guide investigation and molecular confirmation, allowing proper treatment and genetic counseling.

Low-Temperature Solution Crystallization of Nanostructured Oxides and Thin Films.

As an introduction to this themed issue, a critically selected overview of recent progress on the topic of solution methods for the low-temperature crystallization of nanoscale oxide materials is presented. It is focused on the low-temperature solution processing of oxide nanostructures and thin films. Benefits derived from these methods span from minimizing the environmental impact to reducing the fabrication costs. In addition, this topic is regarded as a key objective in the area because it offers a unique opportunity for the use of these materials in areas like flexible electronics, energy conversion and storage, environmental sciences, catalysis, or biomedicine.

A vida pessoal de trabalhadoras do sexo: dilemas de mulheres de classes populares / The private life of sex workers: dilemmas of working class women / La vida personal de trabajadoras del sexo: dilemas de mujeres de clases populares

Resumo O artigo considera como mulheres prostitutas articulam suas relações afetivo-sexuais, condições econômicas e vida profissional. Observando suas experiências e seus relatos de relações com parceiros pessoais, antes e depois do início da prostituição, trata de aproximar a vida e os dilemas de trabalhadoras do sexo dos de outras mulheres, especialmente brasileiras de classes populares. Ao fazê-lo, aborda questões como gênero, maternidade, conjugalidade e suas tensões. Além disso, considera as especificidades de relacionamentos íntimos colocadas pela prostituição, e situações de envolvimento amoroso entre prostitutas e clientes. Atravessando os diversos temas, aparecem conexões entre afetos, sexualidade, dinheiro e trabalho.

Abstract This paper examines how affective and sexual relations, economic issues, and the professional life are articulated by sex workers. Through the observation of their experiences and narratives about personal relationships, before and after starting sex work, their life and dilemmas become closer to those of other women, specifically Brazilian women from lower classes. Issues and tensions of gender, maternity, and conjugality are analyzed; as well as the specificities in romantic relationships created by sex work and romantic involvements between sex workers and clients. Intersected by these themes are connections concerning emotions, sexuality, money and labor.

Resumen El artículo considera como mujeres prostitutas articulan sus relaciones afectivo-sexuales, condiciones económicas y vida profesional. Observando sus experiencias y sus relatos de relaciones con parejas personales, antes y después de su inicio en la prostitución, el análisis intenta aproximar la vida y los dilemas de trabajadoras del sexo a la de otras mujeres, especialmente brasileras de clases populares, luego son abordados asuntos como género, maternidad, conyugalidad y sus tensiones. Además, son consideradas las especificidades de las relaciones íntimas relativas a la prostitución y situaciones de involucramiento amoroso entre prostitutas y clientes. A partir de las intersecciones entre los diversos temas, aparecen conexiones entre afectos, sexualidad, dinero y trabajo.