A proposal for an inclusive working definition of genetic discrimination to promote a more coherent debate.

Genetic discrimination is an evolving phenomenon that impacts fundamental human rights such as dignity, justice and equity. Although, in the past, various definitions to better conceptualize genetic discrimination have been proposed, these have been unable to capture several key facets of the phenomenon. In this Perspective, we explore definitions of genetic discrimination across disciplines, consider criticisms of such definitions and show how other forms of discrimination and stigmatization can compound genetic discrimination in a way that affects individuals, groups and systems. We propose a nuanced and inclusive definition of genetic discrimination, which reflects its multifaceted impact that should remain relevant in the face of an evolving social context and advancing science. We argue that our definition should be adopted as a guiding academic framework to facilitate scientific and policy discussions about genetic discrimination and support the development of laws and industry policies seeking to address the phenomenon.

Integrating hereditary breast and ovarian cancer genetic counselling and testing into mainstream clinical practice: Legal and ethical challenges.

Health professionals not specialized in genetics are expected to take an increasing role in genetic services delivery. This article aims to identify legal and ethical challenges related to a collaborative oncogenetics service model, where non-genetic health professionals provide genetic services to patients. Through a scoping literature review, we identified issues to the provision of hereditary breast and ovarian cancer, or other hereditary adult cancers, genetic testing under this model. Concerns that arose in the literature were informed consent, lack of adherence to best practice guidelines, lack of education of non-genetic health professionals on the provision of genetic services, psychological impacts of genetic testing, continuity of care, the complexity of genetic test results, confidentiality, risks of medical mismanagement, and the associated medical responsibility liabilities. Despite these challenges, there is a growing consensus towards the feasibility of cancer genetic testing being undertaken by non-genetic healthcare professionals in a collaborative oncogenetics service model.

Guiding ATR and PARP inhibitor combinationswith chemogenomic screens.

Combinations of ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis) and poly(ADP-ribose) polymerase inhibitors (PARPis) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this, we performed a genome-wide CRISPR-Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51 paralog mutations, or the "alternative lengthening of telomeres" telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivo dosing schedule. We present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.

De novo duplication on Chromosome 19 observed in nuclear family displaying neurodevelopmental disorders.

Pleiotropy and variable expressivity have been cited to explain the seemingly distinct neurodevelopmental disorders due to a common genetic etiology within the same family. Here we present a family with a de novo 1-Mb duplication involving 18 genes on Chromosome 19. Within the family there are multiple cases of neurodevelopmental disorders including autism spectrum disorder, attention deficit/hyperactivity disorder, intellectual disability, and psychiatric disease in individuals carrying this copy-number variant (CNV). Quantitative polymerase chain reaction (PCR) confirmed the CNV was de novo in the mother and inherited by both sons. Whole-exome sequencing did not uncover further genetic risk factors segregating within the family. Transcriptome analysis of peripheral blood demonstrated a ∼1.5-fold increase in RNA transcript abundance in 12 of the 15 detected genes within the CNV region for individuals carrying the CNV compared with their noncarrier relatives. Examination of transcript abundance across the rest of the transcriptome identified 407 differentially expressed genes (P-value < 0.05; adjusted P-value < 0.1) mapping to immune response, response to endoplasmic reticulum stress, and regulation of epithelial cell proliferation pathways. 16S microbiome profiling demonstrated compositional difference in the gut bacteria between the half-brothers. These results raise the possibility that the observed CNV may contribute to the varied phenotypic characteristics in family members through alterations in gene expression and/or dysbiosis of the gut microbiome. More broadly, there is growing evidence that different neurodevelopmental and psychiatric disorders can share the same genetic variant, which lays a framework for later neurodevelopmental and psychiatric manifestations.