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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

Rare diseases are life-threatening or chronically debilitating conditions affecting millions of people worldwide. In many instances, the patients experience a delay in their diagnosis or remain undiagnosed despite extensive investigations carried out by specialists. There are several explanations to account for this phenomenon including the socioeconomic context and the lack of an established consensus for diagnostic testing. Nonetheless, the widespread use of genetic and genomic tests in the past decades has had a major impact on clinical reasoning paradigms, and new troves of data are constantly being generated and analyzed. This requires constantly updating tools to match the discovery rate and allow reanalysis. In this review, we summarize the latest international recommendations and guidelines to address the problem of diagnostic deficit as well as present the current diagnostic workflows. Increasing access to exome and genome sequencing technologies and biological validation, gaining insight into the interpretation of multi-omics datasets, and fostering data sharing would reduce the long diagnostic odyssey and diagnostic gap. LESS      Full article

Neurogenic dysphagia (ND) is characterized by a swallowing disorder where nervous system, muscle, and neuromuscular diseases are involved. DRD1, COMT, BDNF, and APOE are genes that may have a predictive role in the occurrence and evolution of ND. Many drugs that improve swallowing or can induce or exacerbate swallowing difficulties are related to dopamine metabolism and substance P. These pharmacological treatments for ND include dopamine precursors (levodopa), dopamine agonists (amantadine, apomorphine, cabergoline, and rotigotine), and TRP channel activators (capsaicin, piperine, and menthol). Since treatment outcomes are highly dependent on the genomic profiles of ND patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutic interventions. Knowledge of the pharmacogenetic profiles of these drugs would minimize the occurrence of adverse drug reactions (especially to antidopaminergic medications) that may induce dysphagia and optimize pharmacological treatment that can ameliorate it. This knowledge should also be applied to the use of medications that control symptoms associated with dysphagia, such as sialorrhea, xerostomia, reflux, or hiccups. LESS      Full article