EMQN best practice guidelines for genetic testing in dystrophinopathies.

Dystrophinopathies are X-linked diseases, including Duchenne muscular dystrophy and Becker muscular dystrophy, due to DMD gene variants. In recent years, the application of new genetic technologies and the availability of new personalised drugs have influenced diagnostic genetic testing for dystrophinopathies. Therefore, these European best practice guidelines for genetic testing in dystrophinopathies have been produced to update previous guidelines published in 2010.These guidelines summarise current recommended technologies and methodologies for analysis of the DMD gene, including testing for deletions and duplications of one or more exons, small variant detection and RNA analysis. Genetic testing strategies for diagnosis, carrier testing and prenatal diagnosis (including non-invasive prenatal diagnosis) are then outlined. Guidelines for sequence variant annotation and interpretation are provided, followed by recommendations for reporting results of all categories of testing. Finally, atypical findings (such as non-contiguous deletions and dual DMD variants), implications for personalised medicine and clinical trials and incidental findings (identification of DMD gene variants in patients where a clinical diagnosis of dystrophinopathy has not been considered or suspected) are discussed

The limits of discretion: Challenges and dilemmas of prosecutorial discretion in immigration enforcement

The history of US immigration policy and practice reflects a series of attempts to address complex political demands and organizational tensions. Yet this complexity has rendered comprehensive immigration reform elusive in recent decades. When legislative action appears impossible, what other avenues are available to confront these challenges? During the first term of the Obama administration, prosecutorial discretion emerged as a key mechanism. This article draws on archival data and interviews with immigration attorneys, advocates, analysts, and policy makers to understand better how prosecutorial discretion is used in immigration policy and practice today, why it came to have such a central role, recent challenges to its use, and what these tensions suggests for sociolegal scholarship on immigration. © 2014 American Bar Foundation

Plea Bargaining: The Influence of Counsel

For the criminal defendant, his attorney acts as his loyal and zealous advocate before the court (American Bar Association, 2015), and due process protections of the U.S. adversarial system have afforded this relationship special privilege. In this chapter, we explore the influence and role of the attorney in plea decision making. We first explore the legal context of the attorney’s role in plea bargaining, reviewing several cases that address a defendant’s right to effective assistance of counsel. We then review the shadow of trial theory and other theoretical perspectives as they relate to the attorney’s role in the plea-bargaining process, providing a theoretical background to understand how the attorney’s advice and role likely influence a defendant’s decision to accept a guilty plea offer. Then, we discuss the research examining legal and extra-legal factors that influence the type of advice an attorney gives a client contemplating a guilty plea offer, considering the implications of this research for the current standards used to define effective assistance of counsel. Last, we explore future research possibilities that could contribute to the understanding of the role the attorney plays in the plea-bargaining process

HLA-G genetic diversity and evolutive aspects in worldwide populations

Supplementary Information is available online at: https://www.nature.com/articles/s41598-021-02106-4#Sec11 .HLA-G is a promiscuous immune checkpoint molecule. The HLA-G gene presents substantial nucleotide variability in its regulatory regions. However, it encodes a limited number of proteins compared to classical HLA class I genes. We characterized the HLA-G genetic variability in 4640 individuals from 88 different population samples across the globe by using a state-of-the-art method to characterize polymorphisms and haplotypes from high-coverage next-generation sequencing data. We also provide insights regarding the HLA-G genetic diversity and a resource for future studies evaluating HLA-G polymorphisms in different populations and association studies. Despite the great haplotype variability, we demonstrated that: (1) most of the HLA-G polymorphisms are in introns and regulatory sequences, and these are the sites with evidence of balancing selection, (2) linkage disequilibrium is high throughout the gene, extending up to HLA-A, (3) there are few proteins frequently observed in worldwide populations, with lack of variation in residues associated with major HLA-G biological properties (dimer formation, interaction with leukocyte receptors). These observations corroborate the role of HLA-G as an immune checkpoint molecule rather than as an antigen-presenting molecule. Understanding HLA-G variability across populations is relevant for disease association and functional studies.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil, #302060/2019-7), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil, Finance code: 001), INCTC/FAPESP (Grant #465539/2014-9) for financial support, and FAPESP/Brazil (#Grant 2017/19223-0)

A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G).

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. More than 20 genes with autosomal recessive (LGMD2A to LGMD2Q) and autosomal dominant inheritance (LGMD1A to LGMD1H) have been mapped/identified to date. Mutations are known for six among the eight mapped autosomal dominant forms: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin-3), LGMD1D (desmin), LGMD1E (DNAJB6), and more recently for LGMD1F (transportin-3). Our group previously mapped the LGMD1G gene at 4q21 in a Caucasian-Brazilian family. We now mapped a Uruguayan family with patients displaying a similar LGMD1G phenotype at the same locus. Whole genome sequencing identified, in both families, mutations in the HNRPDL gene. HNRPDL is a heterogeneous ribonucleoprotein family member, which participates in mRNA biogenesis and metabolism. Functional studies performed in S. cerevisiae showed that the loss of HRP1 (yeast orthologue) had pronounced effects on both protein levels and cell localizations, and yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. In vivo analysis showed that hnrpdl is important for muscle development in zebrafish, causing a myopathic phenotype when knocked down. The present study presents a novel association between a muscular disorder and a RNA-related gene and reinforces the importance of RNA binding/processing proteins in muscle development and muscle disease. Understanding the role of these proteins in muscle might open new therapeutic approaches for muscular dystrophies

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study

The common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus fa