Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network.

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

Design and anticipated outcomes of the eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems.

We describe here the design and initial implementation of the eMERGE-PGx project. eMERGE-PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research Network, has three objectives: (i) to deploy PGRNseq, a next-generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1- to 3-year time frame across several clinical sites; (ii) to integrate well-established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record-based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site-specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.

Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update.

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.

Effectiveness of a genetics self-instructional module for nurses involved in egg donor screening.

OBJECTIVE: To evaluate the effectiveness of a self-instructional module in increasing nurses' knowledge of genetics. DESIGN: Pretest/posttest study design. Participants completed a pretest questionnaire used to measure baseline knowledge of basic human genetic concepts and risk assessment and collect descriptive data. Participants then reviewed a self-instructional module and completed a posttest questionnaire. SETTING: Study materials were mailed to 262 registered nurses involved in screening egg donors at 177 reproductive health centers in the United States from July to September 2000. PARTICIPANTS: Sixty-five registered nurses working at reproductive health centers. One hundred of 262 eligible nurses completed the pretest (38% return rate) and 65 of these 100 nurses also completed the posttest (65% retention rate). INTERVENTION: A 22-page self-instructional booklet on genetic risk assessment. MAIN OUTCOME MEASURES: Pretest and posttest responses. RESULTS: There was a significant increase of 20.8% in participants' mean knowledge score on the posttest (M = 89.0%, SD = 8%, range = 67%-100%) as compared with the pretest (M = 69.0%, SD = 12%, range = 42%-92%), based on paired t-test analysis (t = 11.74, SE = 0.426, p < .0001). CONCLUSION: A genetics self-instructional module for registered nurses was effective in increasing knowledge of basic human genetic concepts and risk assessment. More in-depth independent study programs in genetics for nurses are recommended.

Hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is an autosomal recessive iron overload disorder that affects more than one million Americans. This underdiagnosed disorder is associated with high morbidity and mortality, which can be prevented with early identification and treatment. A DNA test that can identify asymptomatic at-risk individuals before biochemical indicators are positive is available commercially. Nurses need current knowledge about HH for two main reasons: (1) to ensure that at-risk individuals receive comprehensive information before genetic testing, and (2) to play a significant role in preventing chronic morbidity and premature death caused by HH.

Preparing the nursing profession for participation in a genetic paradigm in health care.

It is critical that nurses be recognized for their ability to deliver genetic services in collaboration with medical geneticists, genetic counselors, physicians, and providers from other disciplines. The purpose of this special communication is to describe progress made by the International Society of Nurses in Genetics toward incorporating genetics into nursing education and practice.

Beyond Pierre Robin sequence.

The label Pierre Robin sequence is given to infants presenting with a triad of specific congenital anomalies: micrognathia, glossoptosis, and cleft palate. However, this label should be considered the first, not the final, step in the diagnostic process. In approximately 80 percent of newborns with Pierre Robin sequence, the triad of anomalies is part of an underlying genetic condition. This article reviews the variable etiologies of and general clinical considerations for Pierre Robin sequence. To illustrate how clinical management might vary based on the identification of an underlying condition, three case examples of neonates with Pierre Robin sequence and different underlying genetic conditions are presented.

Prader Willi and Angelman syndromes: exemplars of genomic imprinting.

The molecular phenomenon genomic imprinting provides an explanation for why two clinically distinct syndromes share genetic etiologies. Increased understanding of genomic imprinting is affecting diagnostics. Use of improved diagnostic tests can enable early, syndrome-specific, and anticipatory interventions and consequently, improved quality of life; however, these tests are of little use unless clinicians are able to identify at-risk patients. Nurses knowledgeable about Prader Willi and Angelman syndromes and their associated genetic mechanisms can play a significant role in early identification, referral, and intervention of patients with these conditions.

Optimizing drug therapy based on genetic differences: implications for the clinical setting.

Differences in drug responses due to gene alterations are rapidly being identified. Gene alterations may inhibit the function of an enzyme so that an active drug accumulates, causing adverse reactions with normal doses. Alternatively, gene alterations may accelerate enzymatic function so that an active drug is rapidly eliminated, causing subtherapeutic responses to normal doses. Mutations and polymorphisms have been identified that affect a person's response to many currently prescribed medications including cardiovascular, anti-infective, chemotherapeutic, psychiatric, and analgesic drugs. The potential exists for drug therapy to be optimized by selecting medication and doses based on a person's genotype rather than by trial and error. In the near future, advanced practice nurses in the acute care setting may be expected to order, provide patient education about, and explain results of genetic tests before initiating a specific drug therapy. Advanced practice nurses must be knowledgeable about what genetic tests are analyzing and their benefits, limitations, and risks.

Gaucher disease: enzyme therapy in the acute neuronopathic variant.

The responses to regular intravenous enzyme infusions were compared in two sibs with Gaucher disease type 2, the acute neuronopathic variant. Enzyme administration was begun at 7 months in patient 1 who had severe progressive visceral and neuronopathic disease. No significant effect of enzyme infusions was noted. Death occurred at 9 months. Patient 2 was prenatally diagnosed and enzyme infusions were initiated at age 4 days. Overall development progressed at a rate similar to her unaffected full sib until her death at 15.1 months. Slowly progressive esotropia, ocular paresis and dysphagia began at 8 months as did infiltrative pulmonary disease. Comparison of these clinical courses show significant visceral and neurologic effects of anticipatory enzyme therapy, but with unaltered outcome, for Gaucher disease type 2.

Parental consent for bone marrow transplantation in the case of genetic disorders.

PURPOSE: To describe the responses of mothers and fathers who were offered bone marrow transplantation (BMT) for their children with genetic disorders. DESIGN: Qualitative. SETTING: Private hospital rooms/offices. PARTICIPANTS: Six mothers and 4 fathers of children with genetic disorders. RESULTS: The basic social-psychological problem confronting the parents was the conflicting alternatives of life versus death for their children. It was certain that these children would die from their genetic disorders but without having to endure the pain and suffering of a BMT. The BMT would be difficult, possibly resulting in death, but with a chance of survival. CONCLUSIONS: Parents believed that BMT was the only chance of survival for their children, leaving them no choice except to pursue the BMT treatment.

Implementation of a program model to develop specialty staff resource nurses in genetics.

A CNS program to develop staff resource nurses in the specialty area of genetics was implemented. The purpose of the program was to provide staff nurses with necessary knowledge and skills to improve identification of and services for clients with genetic conditions. Twenty-eight staff nurses completed the program, which consisted of a 2-day workshop, a 3-month preceptorship, and regularly scheduled continuing education meetings. Pre- and postworkshop test scores indicated a significant gain in nurses' knowledge of genetic concepts and resources. Resource nurses' interventions with genetic clients increased 3 and 6 months after the workshop. Staff nurse-to-CNS referral of genetic clients continued to increase 3 and 6 months after the workshop. The described program can be used as a model by CNSs in other settings and specialty areas.

Genetic implications of familial adenomatous polyposis: awareness can save lives.

Familial adenomatous polyposis, an inherited condition, can lead to colon cancer if left untreated. Patients seeking treatment for symptoms of this disorder are often found to have cancer already. Because surgical treatment in symptom-free persons with familial adenomatous polyposis greatly reduces their future risk of cancer, presymptomatic identification of the disorder can save lives. Because the disorder is inherited, knowledge of its familial pattern can help nurses recommend candidates for screening. A case study of one family demonstrates the value of genetic analysis and the role nurses can play.

Nature and prevalence of ribavirin aerosol administration in U.S. pediatric hospitals.

A survey was undertaken to determine the nature and prevalence of ribavirin aerosol administration in pediatric hospitals. Ribavirin was administered in 79.4% of the respondents' hospitals. The majority used head hoods for aerosol administration. Ventilators were the primary method used by 6% of the respondents. This study demonstrates typical types of ribavirin exposure and the need to evaluate effects of chronic exposure.

Utilization of genetic knowledge in pediatric nursing practice.

Many clients with potential genetic conditions are leaving clinics and hospitals without the conditions being recognized. Nurses knowledgeable in genetics can change this by using skills in genetic history-taking and dysmorphology assessment to recognize signs of genetic conditions and birth defects. Nurses can also positively impact clients' health by participating in follow-up care after a genetic evaluation and counseling. During any interaction, nurses need to be advocates for genetic clients.