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Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all NF1^+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1^-/- cells; however, by restoring function in the surrounding NF1^+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1^-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations. This review describes the rationale for NF1-HCT, including specific NF1 considerations (e.g., NF1 clinical phenotype, neurofibromin function/regulation, NF1 mutational spectrum, genotype-phenotype correlation, and the impact of haploinsufficiency in NF1), HCT in other haploinsufficient diseases, potential NF1-HCT drug treatment strategies, and the potential advantages/challenges of NF1-HCT. LESS      Full article

Coronary artery disease (CAD) is a pandemic disease and the number one cause of death in the world. Predisposition to CAD is about 50% acquired and 50% genetic. CAD prevention has been proven in randomized clinical trials with statin therapy. However, primary prevention is limited by the lack of biomarkers to detect asymptomatic young individuals at risk. Traditional risk factors (TRFs) such as hypertension or Type 2 Diabetes are age-dependent and often not present until the sixth or seventh decade. In contrast, genetic risk determined at conception is potentially a biomarker to detect young individuals at risk for CAD. The first genetic risk variant for CAD (9p21) was discovered in 2007, and subsequently, over 200 risk variants for CAD were discovered. A genetic risk score (GRS) based on the genetic risk variants for CAD was evaluated in over one million individuals. Retrospective analysis of clinical trials assessing the effect of statin therapy showed that individuals with the highest GRS had the highest risk for cardiac events and also the most benefit from lowering cholesterol. In a recent study of 55,685 individuals, those with the highest GRS (20%) had a 91% higher risk for cardiac events. Furthermore, those with high genetic risk on a favorable lifestyle had 46% fewer cardiac events than those with an unfavorable lifestyle. The GRS is superior and independent of TRFs. Incorporation into clinical practice will be a paradigm shift in preventing this pandemic. LESS      Full article

Aim: Long QT syndrome (LQTS) is an inherited condition that predisposes individuals to prolongation of the QT interval and increased risk for Torsade de Pointes. Pathogenic variants in three genes - KCNH2, KCNQ1 and SCN5A - are responsible for most cases of LQTS, and recent advances in genetic testing have improved knowledge of the disease, increased access to follow-up, and reduced adverse cardiovascular outcomes. Methods: Based around our preemptive genetic screening platform which includes the three long QT genes listed above, we developed and implemented a clinical decision support (CDS) module that alerts prescribers whenever a QT-prolonging medication is ordered for patients with a genetic predisposition to LQTS. Results: Of the 13,777 individuals screened, twenty-seven tested positive for a pathogenic or likely pathogenic variant of KCNH2, KCNQ1 or SCN5A. In a subsequent early evaluation of the CDS and clinical processes, the number of QT-prolonging medications in this cohort decreased by 20% and new QT-prolonging medications were avoided in approximately 1/3 of new prescription orders. Conclusions: While long-term evaluation is needed, early data support the benefit of utilizing CDS in expanded roles, such as drug-gene-disease interactions where rare genetic variants intersect with everyday prescribing. LESS      Full article

PM20D1 is a little studied enzyme until recently, belonging to the mammalian M20 peptidase family, which catalyzes both the synthesis and hydrolysis of N-acyl amino acids (NAAs). NAAs are bioactive lipids biosynthesized from free fatty acids and free amino acids. These molecules have been associated with many biological functions; however, most of the biochemical mechanisms have not yet been described. The best-known biochemical mechanism is the one involved in thermogenesis, which also has implications for reactive oxygen species levels and cell preservation. In the last few years, genetic variation in PM20D1, as well as changes in its methylation and expression levels, have been reported to be associated with several disease phenotypes, including Alzheimer’s disease. In this review, we explore the current knowledge regarding the PM20D1 gene, including aspects such as its biology, potential functions, regulation of its expression, and role in different phenotypes such as Alzheimer’s disease, obesity, Parkinson’s disease, and several other disorders. LESS      Full article

The purpose of this abstract is to provide data on a 27-year-old woman with a rare and rapidly progressive cancer, Nuclear in Testis (NUT) carcinoma (NC), and to highlight possible treatment options for her specific gene translocation of NSD3-NUT. To our knowledge, this is the first case in the literature that was presented initially as anaplastic thyroid cancer. We propose that targeted therapy with a histone lysine methyltransferase inhibitor may be of benefit as adjunctive therapy in patients with the NSD3-NUT gene translocation. LESS      Full article

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting at least 1 in 2500 individuals. CMT refers to a heterogeneous group of inherited neuropathies from both phenotypic and genetic points of view. Over the last decades, there have been important advances not only in the identification of causative genes but also in understanding the molecular basis for many forms of CMT. In fact, to date, around 100 genes have been related to CMT disease, thanks to next generation sequencing techniques, and they have been proven to affect either the myelin or axon of peripheral nerves. Moreover, its genetic diagnosis has remarkedly improved, although there are still difficulties when it comes to treatment. In this review, we explore in depth the eight most prevalent genes associated with CMT: GDAP1, GJB1, HINT1, MFN2, MPZ, PMP22, SH3TC2, and SORD. We also address the disrupted cellular processes and pathophysiological mechanisms involved in the disease. A better understanding of the pathogenic mechanisms responsible for each type of CMT would be essential to identifying molecular targets and therapeutic strategies. LESS      Full article