Pharmacogenomics has been at the forefront of precision medicine during the last few decades. Precision medicine carries the potential of improving health outcomes at both the individual as well as ...population levels. To harness the benefits of its initiatives, careful dissection of existing health disparities as they relate to precision medicine is of paramount importance. Attempting to address the existing disparities at the early stages of design and implementation of these efforts is the only guarantee of a successful just outcome. In this review, we glance at a few determinants of existing health disparities as they intersect with pharmacogenomics research and implementation. In our opinion, highlighting these disparities is imperative for the purpose of researching meaningful solutions. Failing to identify, and hence address, these disparities in the context of the current and future precision medicine initiatives would leave an already strained health system, even more inundated with inequality.
Abstract Pediatric cardiomyopathies are mostly attributed to variants in sarcomere-related genes. Unfortunately, the genetic architecture of pediatric cardiomyopathies has never been previously ...studied in Jordan. We sought to uncover the genetic landscape of 14 patients from nine families with several subtypes of pediatric cardiomyopathies in Jordan using Exome sequencing (ES). Our investigation identified pathogenic and likely pathogenic variants in seven out of nine families (77.8%), clustering in sarcomere-related genes. Surprisingly, phenocopies of sarcomere-related hypertrophic cardiomyopathies were evident in probands with glycogen storage disorder and mitochondrial-related disease. Our study underscored the significance of streamlining ES or expanding cardiomyopathy-related gene panels to identify plausible phenocopies of sarcomere-related cardiomyopathies. Our findings also pointed out the need for genetic testing in patients with cardiomyopathy and their at-risk family members. This can potentially lead to better management strategies, enabling early interventions, and ultimately enhancing their prognosis. Finally, our findings provide an initial contribution to the currently absent knowledge about the molecular underpinnings of cardiomyopathies in Jordan.
•FMR1-CGG repeat’s expansion is associated with primary ovarian insufficiency.•Short FMR1-CGG repeats are associated with poor ovarian response.•FMR1-CGG allele length is not correlated with markers ...of ovarian reserve.
The expansion of trinucleotide CGG repeats in the promoter of fragile X mental retardation 1 (FMR1) gene is associated with fragile X and fragile X associated tremor/ataxia syndromes. While the expansion of CGG repeats has been associated with such neuro/psychiatric diseases, the contraction of CGG repeats has been recently suggested as an indication of ovarian dysfunction. This study aimed to evaluate a possible association of the short CGG repeats with poor ovarian responders (POR) and to test for a possible correlation between the CGG size and different known markers of the ovarian reserve, namely FSH, AMH, and the number of retrieved oocytes from Jordanian females. We found a significant difference between the CGG median allele size between the cases and the controls (p < 0.001), where poor ovarian responders had shorter CGG repeats compared to the healthy controls. Also, females with alleles <26 had twice the odds to be presented in the POR compared to the controls. However, we did not find a significant correlation between CGG sizes and the markers of ovarian reserve. We conclude that although low CGG repeats appear to be linked to POR, the clinical utility of FMR1 for predicting ovarian response needs further investigation.
Genetic testing has the potential to revolutionize primary care, but few health systems have developed the infrastructure to support precision population medicine applications or attempted to ...evaluate its impact on patient and provider outcomes. In 2018, Sanford Health, the nation's largest rural nonprofit health care system, began offering genetic testing to its primary care patients. To date, more than 11,000 patients have participated in the Sanford Chip Program, over 90% of whom have been identified with at least one informative pharmacogenomic variant, and about 1.5% of whom have been identified with a medically actionable predisposition for disease. This manuscript describes the rationale for offering the Sanford Chip, the programs and infrastructure implemented to support it, and evolving plans for research to evaluate its real-world impact.
Staphylococcus genus is a Gram-positive coccus normally associated with skin and mucous membranes of warm-blooded animals. It is part of the commensal human microflora, or found in animals, or ...contaminating surfaces in the community and hospital settings. Staphylococcus aureus is the most pathogenic species belonging to this genus, as it possesses a collection of virulence factors that are expressed solely to evade the immune system. The increase in the misuse of antimicrobial agents predisposed S. aureus to develop antibiotic resistance, including the resistance to methicillin which led to the emergence of Methicillin-Resistant S. aureus (MRSA). MRSA is considered one of the most dangerous nosocomial pathogens causing many hard to treat infections in hospitals and was named as Hospital Associated MRSA (HA-MRSA). Over the past 20-25 years, MRSA was isolated from community settings and thus Community Associated MRSA (CA-MRSA) has emerged. Inside hospitals, MRSA has been isolated from fomites in contact with patients, as well as staff's protective and personal items. This review highlights the worldwide prevalence of MRSA on fomites within the contexts of hospital and community settings.
Poor ovarian response (POR) refers to a subnormal follicular response that leads to a decrease in the quality and quantity of the eggs retrieved after ovarian stimulation during assisted reproductive ...treatment (ART). The present study investigated the associations of multiple variants of the estrogen receptor 2 (ESR2) and follicle-stimulating hormone receptor (FSHR) genes with POR in infertile Jordanian women undergoing ART.
Four polymorphisms, namely ESR2 rs1256049, ESR2 rs4986938, FSHR rs6165, and FSHR rs6166, were investigated in 60 infertile Jordanian women undergoing ART (the case group) and 60 age-matched fertile women (the control group), with a mean age of 33.60±6.34 years. Single-nucleotide polymorphisms (SNPs) were detected by restriction fragment length polymorphism and then validated using Sanger sequencing.
The p-value of the difference between the case and control groups regarding FSHR rs6166 was very close to 0.05 (p=0.054). However, no significant differences were observed between the two groups in terms of the other three SNPs, namely ESR2 rs1256049, ESR2 rs4986938, and FSHR rs6165 (p=0.561, p=0.433, and p=0.696, respectively).
The association between FSHR rs6166 and POR was not statistically meaningful in the present study, but the near-significant result of this experiment suggests that statistical significance might be found in a future study with a larger number of patients.
Abstract
Background
Pharmacogenetics or pharmacogenomics (PGx) is the study of the role of inherited or acquired sequence change in drug response. With the rapid evolution of molecular techniques, ...bioinformatic tools, and increased throughput of functional genomic studies, the discovery of PGx associations and clinical implementation of PGx test results have now moved beyond a handful variants in single pharmacogenes and multi-gene panels that interrogate a few pharmacogenes to whole-exome and whole-genome scales. Although some laboratories have adopted next-generation sequencing (NGS) as a testing platform for PGx and other molecular tests, most clinical laboratories that offer PGx tests still use targeted genotyping approaches.
Content
This article discusses primarily the technical considerations for clinical laboratories to develop NGS-based PGx tests including whole-genome and whole-exome sequencing analyses and highlights the challenges and opportunities in test design, content selection, bioinformatic pipeline for PGx allele and diplotype assignment, rare variant classification, reporting, and briefly touches a few additional areas that are important for successful clinical implementation of PGx results.
Summary
The accelerated speed of technology development associated with continuous cost reduction and enhanced ability to interrogate complex genome regions makes it inevitable for most, if not all, clinical laboratories to transition PGx testing to an NGS-based platform in the near future. It is important for laboratories and relevant professional societies to recognize both the potential and limitations of NGS-based PGx profiling, and to work together to develop a standard and consistent practice to maximize the variant or allele detection rate and utility of PGx testing.
Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast ...fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk
zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.
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