Evidence of the high prevalence of neurological disorders in nonsyndromic X-linked recessive ichthyosis: a retrospective case series

[Background]: X-linked recessive ichthyosis (XLI) is a relatively common type of ichthyosis caused by a deficiency in the steroid sulfatase (STS) enzyme. It is the only type of ichthyosis that can be both syndromic and nonsyndromic. Typical clinical features include dark-brown scale of variable size favouring the extensor surfaces of the extremities.[Objectives]: To characterize clinically nonsyndromic XLI, with a particular focus on extracutaneous manifestations.[Methods]: This was a multicentre retrospective review of clinical findings from a case series of patients with a clinical and genetic diagnosis of XLI.[Results]: We identified 30 patients with XLI belonging to 25 different families carrying a deletion in the STS locus. All patients had dark scales of variable size on the extensor surfaces of the extremities. Lack of flexural involvement and pruritus were common but inconsistent findings, whereas palmoplantar hyperlinearity was absent in all but one patient. A history of orchiopexy was present in 10% and thus was more common than expected vs. the general population (3%). Neurological disorders including epilepsy (13%) and attention deficit hyperactivity disorder (ADHD; 30%) were over-represented in patients with XLI.[Conclusions]: This was a retrospective study with a limited number of patients. In the absence of confirmatory genetic testing and family history of the disease, dark-brown scale of the extensor surfaces and the absence of palmoplantar hyperlinearity appear to be the most reliable clinical findings supporting a diagnosis of XLI. Dermatologists should be aware of the high prevalence of ADHD and epilepsy in patients with nonsyndromic XLI

Threats to the validity of the Collegiate Learning Assessment (CLA+) as a measure of critical thinking skills and implications for Learning Gain

The University of Reading Learning Gain project is a three-year longitudinal project to test and evaluate a range of available methodologies and to draw conclusions on what might be the right combination of instruments for the measurement of Learning Gain in higher education. This paper analyses the validity of a measure of critical thinking skills, the Collegiate Learning Assessment (CLA+) and the implications of using this standardised test as a proxy for Learning Gain. The paper reviews five inferences regarding the interpretations and use of test scores: construct representation, scoring, generalisation, extrapolation and decision-making. Each section reviews some of the available evidence in support of the claims the CLA+ makes and the threats to their validity. The possible impact of these issues on Learning Gain in the UK is considered

Comprehensive functional characterization and clinical interpretation of 20 splice-site variants of the RAD51C gene

Simple SummaryGenetic variants in more than 10 genes are known to confer moderate to high risks to breast and/or ovarian cancers (BC/OC). In the framework of the international project BRIDGES, a panel of 34 known or suspected BC/OC genes has been sequenced in 60,466 breast cancer patients and 53,461 controls. In this work, we focus on BRIDGES variants detected in the RAD51C gene and their impact on the gene expression step known as splicing (intron removal), whose alteration is a relevant disease mechanism. For this purpose, we bioinformatically analyzed 40 RAD51C variants from the intron/exon boundaries, 20 of which were selected. Then, we developed a biotechnological tool, called splicing reporter minigene, containing RAD51C exons 2 to 8 where any variant can be introduced by site-directed mutagenesis and functionally assayed in MCF-7 cells under the splicing perspective. Nineteen variants impaired splicing, 18 of which induced severe splicing anomalies. Finally, they were clinically interpreted according to strict guidelines whereby 15 variants were classified as Pathogenic/Likely Pathogenic, so they are clinically actionable. Therefore, carrier patients and families may benefit from tailored prevention protocols and therapies.Hereditary breast and/or ovarian cancer is a highly heterogeneous disease with more than 10 known disease-associated genes. In the framework of the BRIDGES project (Breast Cancer Risk after Diagnostic Gene Sequencing), the RAD51C gene has been sequenced in 60,466 breast cancer patients and 53,461 controls. We aimed at functionally characterizing all the identified genetic variants that are predicted to disrupt the splicing process. Forty RAD51C variants of the intron-exon boundaries were bioinformatically analyzed, 20 of which were selected for splicing functional assays. To test them, a splicing reporter minigene with exons 2 to 8 was designed and constructed. This minigene generated a full-length transcript of the expected size (1062 nucleotides), sequence, and structure (Vector exon V1- RAD51C exons_2-8- Vector exon V2). The 20 candidate variants were genetically engineered into the wild type minigene and functionally assayed in MCF-7 cells. Nineteen variants (95%) impaired splicing, while 18 of them produced severe splicing anomalies. At least 35 transcripts were generated by the mutant minigenes: 16 protein-truncating, 6 in-frame, and 13 minor uncharacterized isoforms. According to ACMG/AMP-based standards, 15 variants could be classified as pathogenic or likely pathogenic variants: c.404G > A, c.405-6T > A, c.571 + 4A > G, c.571 + 5G > A, c.572-1G > T, c.705G > T, c.706-2A > C, c.706-2A > G, c.837 + 2T > C, c.905-3C > G, c.905-2A > C, c.905-2_905-1del, c.965 + 5G > A, c.1026 + 5_1026 + 7del, and c.1026 + 5G > T.Molecular tumour pathology - and tumour geneticsMTG1 - Moleculaire genetica en pathologie van borstkanke

Splicing predictions, minigene analyses, and ACMG-AMP clinical classification of 42 germline PALB2 splice-site variants

PALB2 loss-of-function variants confer high risk of developing breast cancer. Here we present a systematic functional analysis of PALB2 splice-site variants detected in approximately 113,000 women in the large-scale sequencing project Breast Cancer After Diagnostic Gene Sequencing (BRIDGES; ). Eighty-two PALB2 variants at the intron-exon boundaries were analyzed with MaxEntScan. Forty-two variants were selected for the subsequent splicing functional assays. For this purpose, three splicing reporter minigenes comprising exons 1-12 were constructed. The 42 potential spliceogenic variants were introduced into the minigenes by site-directed mutagenesis and assayed in MCF-7/MDA-MB-231 cells. Splicing anomalies were observed in 35 variants, 23 of which showed no traces or minimal amounts of the expected full-length transcripts of each minigene. More than 30 different variant-induced transcripts were characterized, 23 of which were predicted to truncate the PALB2 protein. The pathogenicity of all variants was interpreted according to an in-house adaptation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) variant classification scheme. Up to 23 variants were classified as pathogenic/likely pathogenic. Remarkably, three +/- 1,2 variants (c.49-2A>T, c.108+2T>C, and c.211+1G>A) were classified as variants of unknown significance, as they produced significant amounts of either in-frame transcripts of unknown impact on the PALB2 protein function or the minigene full-length transcripts. In conclusion, we have significantly contributed to the ongoing effort of identifying spliceogenic variants in the clinically relevant PALB2 cancer susceptibility gene. Moreover, we suggest some approaches to classify the findings in accordance with the ACMG-AMP rationale. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.Genome Instability and Cance

Comportamento de poedeiras criadas a diferentes densidades e tamanhos de grupo em ambiente enriquecido

O objetivo deste trabalho foi determinar diferenças comportamentais entre poedeiras criadas sob diferentes densidades e tamanhos de grupo, em condições de ambiente enriquecido. Foram utilizadas poedeiras Isa Brown com idade entre 30 e 32 semanas alojadas em galpões de escala reduzida e distorcida. As aves foram criadas durante 28 dias, em baias com cama de maravalha, poleiro e ninho. Foram avaliados dois tamanhos de grupos (6 e 12 aves) e duas densidades de criação (774 e 1.440 cm² por ave), em arranjo fatorial com três repetições. Em amostras de vídeo de 15 min, foram registrados as frequências e os tempos de expressão dos comportamentos: arrumar penas, banho de areia, bater asas, beber água, bicar, coçar a cabeça, ciscar, comer, empoleirar, esticar perna, perseguir, sentar e visitar o ninho. Foram observados efeitos significativos dos tratamentos e da interação entre eles. O grupo de seis aves manifestou aumento da frequência de comportamentos que indicam maior frustração das aves, independentemente da densidade. O tamanho de grupo é o fator mais importante para o bem-estar das aves

Xaraés palisadegrass remains productive after the disappearance of stylo in tropical legume-grass pasture

Gradual reduction of legumes in mixed tropical pastures requires periodic oversowing. Exploiting the carrying capacity of grass for an extra year after the disappearance of legumes can be economically advantageous to the farmer. This study aimed to evaluate the productivity of Xaraés palisadegrass (Brachiaria brizantha) pastures in response to its historical association with stylo (Stylosanthes guianensis) under two canopy heights to determine whether different grazing management conditions affect the defoliation pattern left by grazing animals. The split-plot experimental design was used, with the historical botanical composition (HBC) (24, 34, 45 and 52 % legume composition) corresponding to the main plots and the canopy frequency of defoliation determined at heights of 30 and 45 cm for Xaraés palisadegrass corresponding to the subplots with two replicates (500 m2) grazed by Tabapuã cows. Pastures with over 34 % stylo in the botanical composition remained productive for one year after legume disappearance, accumulating more than 8 mg ha−1 of forage per year. Xaraés palisadegrass pastures at a height of 30 cm provided better canopy structure, with 64 % less stem production and 43 % less dead material. The 30-cm pre-grazing canopy height provided a grazing environment conducive to forage intake by animals that resulted in efficient use of the pasture. In response to the improved canopy structure, the cows grazed an average of 60 fewer minutes. A HBC greater than 34 % of legumes in the pastures allows for the postponement of legume oversowing until the next growing season