In clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing, which emphasized the importance of disclosing the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. We recommend that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the ‘normal’ of tumor-normal subtractive analyses in all subjects, irrespective of age, but excluding fetal samples. We recognize that there are insufficient data on clinical utility to fully support these recommendations and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.

CHARGE association is a nonrandom pattern of congenital anomalies that occurs together more frequently than one would expect on the basis of chance. This common multiple anomaly condition has an estimated prevalence of 1:10,000. The number of children diagnosed with CHARGE association is increasing, owing presumably to greater awareness of this condition and advances in the care of complex, chronically ill children, resulting in improved survival and outcome. This review of CHARGE association presents diagnostic criteria that may define a concise, recognizable syndrome with a single pathogenetic basis. This review also summarizes our current understanding of the management for this complex and chronic multiple congenital anomaly condition and discusses the pathogenetic basis for this condition.

The Electronic Medical Records and Genomics (eMERGE) Network is a National Human Genome Research Institute (NHGRI)-funded consortium engaged in the development of methods and best-practices for utilizing the Electronic Medical Record (EMR) as a tool for genomic research. Now in its sixth year, its second funding cycle and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from EMRs can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and healthcare informatics, particularly electronic phenotyping, genome-wide association studies, genomic medicine implementation and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here we describe the evolution, accomplishments, opportunities and challenges of the network since its inception as a five-group consortium focused on genotype-phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting towards implementation of genomic medicine.

Although the potential for genomics to contribute to clinical care has long been anticipated, the pace of defining the risks and benefits of incorporating genomic findings into medical practice has been relatively slow. Several institutions have recently begun genomic medicine programs, encountering many of the same obstacles and developing the same solutions, often independently. Recognizing that successful early experiences can inform subsequent efforts, the National Human Genome Research Institute brought together a number of these groups to describe their ongoing projects and challenges, identify common infrastructure and research needs, and outline an implementation framework for investigating and introducing similar programs elsewhere. Chief among the challenges were limited evidence and consensus on which genomic variants were medically relevant; lack of reimbursement for genomically driven interventions; and burden to patients and clinicians of assaying, reporting, intervening, and following up genomic findings. Key infrastructure needs included an openly accessible knowledge base capturing sequence variants and their phenotypic associations and a framework for defining and cataloging clinically actionable variants. Multiple institutions are actively engaged in using genomic information in clinical care. Much of this work is being done in isolation and would benefit from more structured collaboration and sharing of best practices.Genet Med 2013:15(4):258–267

As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.

INTRODUCTIONReporting and sharing pharmacogenetic test results across clinical laboratories and electronic health records is a crucial step toward the implementation of clinical pharmacogenetics, but allele function and phenotype terms are not standardized. Our goal was to develop terms that can be broadly applied to characterize pharmacogenetic allele function and inferred phenotypes.MATERIALS AND METHODSTerms currently used by genetic testing laboratories and in the literature were identified. The Clinical Pharmacogenetics Implementation Consortium (CPIC) used the Delphi method to obtain consensus and agree on uniform terms among pharmacogenetic experts.RESULTSExperts with diverse involvement in at least one area of pharmacogenetics (clinicians, researchers, genetic testing laboratorians, pharmacogenetics implementers, and clinical informaticians; n=58) participated. After completion of five surveys, consensus (>70%) was reached with 90% of experts agreeing to the final sets of pharmacogenetic terms.DISCUSSIONThe proposed standardized pharmacogenetic terms will improve the understanding and interpretation of pharmacogenetic tests and reduce confusion by maintaining consistent nomenclature. These standard terms can also facilitate pharmacogenetic data sharing across diverse electronic health care record systems with clinical decision support.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines.

The epidemiology and natural history of pediatric primary sclerosing cholangitis (PSC), autoimmune sclerosing cholangitis (ASC), and autoimmune hepatitis (AIH) are not well characterized. Using multiple, overlapping search strategies followed by a detailed records review, we identified all cases of pediatric PSC, ASC, AIH, and inflammatory bowel disease (IBD) in a geographically isolated region of the United States. We identified 607 cases of IBD, 29 cases of PSC, 12 cases of ASC, and 44 cases of AIH. The mean age at diagnosis was 13.0 years for PSC, 11.3 years for ASC, and 9.8 years for AIH. The incidence and prevalence of PSC, ASC, and AIH were 0.2 and 1.5 cases, 0.1 and 0.6 cases, and 0.4 and 3.0 cases per 100,000 children, respectively. The mean duration of follow-up was 5.9 years. The probability of developing complicated liver disease within 5 years of the diagnosis of liver disease was 37% [95% confidence interval (CI) 5 21%-58%] for PSC, 25% (95% CI 5 7%-70%) for ASC, and 15% (95% CI 5 7%-33%) for AIH. The 5-year survival rates with the native liver were 78% (95% CI 5 54%-91%) for PSC, 90% (95% CI 5 47%-99%) for ASC, and 87% (95% CI 5 71%-95%) for AIH. Cholangiocarcinoma developed in 2 of the 29 PSC patients (6.9%). PSC occurred in 9.9% of patients with ulcerative colitis (UC) and in 0.6% of patients with Crohn's disease (CD). ASC occurred in 2.3% of UC patients and 0.9% of CD patients. AIH occurred in 0.4% of UC patients and in 0.3% of CD patients. Liver disease occurred in 39 of 607 IBD patients (6.4%) overall. Conclusion: Immune-mediated liver diseases are important sources of morbidity in children. Using a populationbased design, this study quantifies the burden and natural history of immune-mediated liver disease in children. (HEPATOLOGY 2013;58:1392-1400