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.

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Background The cost of genomic information has fallen steeply but the path to clinical translation of risk estimates for common variants found in genome wide association studies remains unclear. Since the speed and cost of sequencing complete genomes is rapidly declining, more comprehensive means of analyzing these data in concert with rare variants for genetic risk assessment and individualisation of therapy are required. Here, we present the first integrated analysis of a complete human genome in a clinical context. Methods An individual with a family history of vascular disease and early sudden death was evaluated. Clinical assessment included risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome sequence data including 2.6 million single nucleotide polymorphisms and 752 copy number variations. The algorithm focused on predicting genetic risk of genes associated with known Mendelian disease, recognised drug responses, and pathogenicity for novel variants. In addition, since integration of risk ratios derived from case control studies is challenging, we estimated posterior probabilities from age and sex appropriate prior probability and likelihood ratios derived for each genotype. In addition, we developed a visualisation approach to account for gene-environment interactions and conditionally dependent risks. Findings We found increased genetic risk for myocardial infarction, type II diabetes and certain cancers. Rare variants in LPA are consistent with the family history of coronary artery disease. Pharmacogenomic analysis suggested a positive response to lipid lowering therapy, likely clopidogrel resistance, and a low initial dosing requirement for warfarin. Many variants of uncertain significance were reported. Interpretation Although challenges remain, our results suggest that whole genome sequencing can yield useful and clinically relevant information for individual patients, especially for those with a strong family history of significant disease.

IMPORTANCE Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. OBJECTIVES To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. DESIGN, SETTING, AND PARTICIPANTS An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. MAIN OUTCOMES AND MEASURES Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. RESULTS Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95%CI, 0.40-0.64), and reclassified 69%of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001). CONCLUSIONS AND RELEVANCE In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. These recommendations are relevant to families, clinicians, and investigators. After a brief review of the 1995 statement and major changes in genetic technologies in recent years, this statement offers points to consider on a broad range of test technologies and their applications in clinical medicine and research. Recommendations are also made for record and communication issues in this domain and for professional education.

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.

The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.

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