Detection of mosaic variants using genome sequencing in a large pediatric cohort

The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.     

Neuroproteomics of the synapse and drug addiction

Proteomic analyses of brain tissues are becoming an integral component of neuroscientific research. In particular, the essential role of the synapse in neurotransmission and plasticity has brought about extensive efforts to identify its protein constituents. Recent studies have used a combination of subcellular fractionation and proteomic techniques to identify proteins associated with different components of the synapse. Thus, a coherent map of the synapse proteome is rapidly emerging, and a timely review of these data is warranted. In the first part of this review, neuroproteomic techniques that have been used to analyze the synapse proteome are described. We then summarize the results from several recent proteomic analyses of mammalian synapses and discuss the similarities and differences in their profiling of synaptic proteins. Important advances in this field of research include the use of proteomics to analyze synaptic function and drug effects on synaptic proteins. This article presents an overview of proteomic analyses of the phosphorylation states of synaptic proteins and recent applications of neuroproteomic techniques to the study of drug addiction. Finally, we discuss the challenges in comparing proteomic studies of drug addiction and the future directions of this field in furthering our understanding of the molecular mechanisms underlying synaptic function and drug addiction.     

Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.

Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 microg) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 microg i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 microg) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.     

CDH1 pathogenic variants and cancer risk in an unselected patient population

Familial Cancer - CDH1 pathogenic variants confer a markedly elevated lifetime risk of developing diffuse gastric cancer (DGC) and lobular breast cancer (LBC). The aim of this study was to evaluate...     

Perspectives of diverse Spanish- and English-speaking patients on the clinical use of polygenic risk scores

PurposeAs polygenic risk scores (PRS) emerge as promising tools to inform clinical care, there is a pressing need for patient-centered evidence to guide their implementation, particularly in diverse populations. Here, we conducted in-depth interviews of diverse Spanish- and English-speaking patients to explore their perspectives on clinical PRS.MethodsWe enrolled 30 biobank participants aged 35-50 years through a purposive sampling strategy, ensuring that >75% self-reported as African/African American or Hispanic/Latinx and half were Spanish-speaking. Semistructured interviews in Spanish or English explored attitudes toward PRS, barriers to adoption, and communication preferences. Data were analyzed using an inductive thematic analysis approach.ResultsPerceived utility of clinical PRS focused on the potential for personal health benefits, and most participants stated that high-risk results would prompt physician consultations and health behavior changes. There was little concern among participants about the limited predictive power of PRS for non-European populations. Barriers to uptake of PRS testing and adoption of PRS-related recommendations included socioeconomic factors, insurance status, race, ethnicity, language, and inadequate understanding of PRS. Participants favored in-person PRS result disclosure by their physician.ConclusionFindings provide valuable insight into diverse patients’ attitudes and potential barriers related to clinical PRS, guiding future research and patient-centered clinical implementation.     

Conflict and HIV: A framework for risk assessment to prevent HIV in conflict-affected settings in Africa

In sub-Saharan Africa, HIV/AIDS and violent conflict interact to shape population health and development in dramatic ways. HIV/AIDS can create conditions conducive to conflict. Conflict can affect the epidemiology of HIV/AIDS. Conflict is generally understood to accelerate HIV transmission, but this view is simplistic and disregards complex interrelationships between factors that can inhibit and accelerate the spread of HIV in conflict and post conflict settings, respectively. This paper provides a framework for understanding these factors and discusses their implications for policy formulation and program planning in conflict-affected settings.