Advances in clinical genetics and its current challenges.

The great advances in the development of genomic technologies and their incorporation into routine clinical practice is bringing about a change in which an individual's genetic information is becoming increasingly relevant to their medical care. This is known as genomic medicine. Its implementation is not without barriers, including difficulties in the assessment and interpretation of genomic data, deficient training of professionals and patients in this field, unequal access to units with expertise, and a lack of professional profiles and infrastructures necessary for the incorporation of genomic technologies into routine clinical practice. This article reviews the advances and challenges of genomic medicine.

Canadian College of Medical Geneticists (CCMG) points to consider: resuming genetic services in a pandemic-a summary.

The COVID-19 pandemic has disrupted the provision of genetic care in Canada. With the public health effort to flatten the curve, many clinics have moved to virtual care for select populations of patients while triaging and postponing others. As genetic services are asked to gradually resume, a roadmap is needed to ensure clinical care decisions for at-risk patients are transparent and equitable, that postponed care is resumed and that patients with or waiting for a genetic diagnosis are not disproportionately affected or abandoned.The purpose of this document is to highlight the guiding ethical principles and stakeholder considerations in resuming genetic services to help guide the competing needs going forward of both limiting exposures while maintaining high-quality care. Considerations highlighted are (1) environment of practice, (2) nature of consult, (3) patient factors, (4) provider factors, and (5) laboratory factors. The intended users are those providing genetic care in a Canadian context with the recognition that there are clinic-specific and regional variations that will influence decision-making. While specific to the Canadian context, the ethical principles used to guide these decisions would be relevant for consideration in other jurisdictions.

Clan genomics: From OMIM phenotypic traits to genes and biology.

Clinical characterization of a patient phenotype has been the quintessential approach for elucidating a differential diagnosis and a hypothesis to explore a potential clinical diagnosis. This has resulted in a language of medicine and a semantic ontology, with both specialty- and subspecialty-specific lexicons, that can be challenging to translate and interpret. There is no 'Rosetta Stone' of clinical medicine such as the genetic code that can assist translation and interpretation of the language of genetics. Nevertheless, the information content embodied within a clinical diagnosis can guide management, therapeutic intervention, and potentially prognostic outlook of disease enabling anticipatory guidance for patients and families. Clinical genomics is now established firmly in medical practice. The granularity and informative content of a personal genome is immense. Yet, we are limited in our utility of much of that personal genome information by the lack of functional characterization of the overwhelming majority of computationally annotated genes in the haploid human reference genome sequence. Whereas DNA and the genetic code have provided a 'Rosetta Stone' to translate genetic variant information, clinical medicine, and clinical genomics provide the context to understand human biology and disease. A path forward will integrate deep phenotyping, such as available in a clinical synopsis in the Online Mendelian Inheritance in Man (OMIM) entries, with personal genome analyses.

The International Human Genome Project.

The human genome project was conceived and executed as an international project, due to both pragmatic and principled reasons. This internationality has served the project well, with the resulting human genome being freely available for all researchers in all countries. Over time the reference human genome will likely have to evolve to a graph genome, and tap into more diverse sequences worldwide. A similar international mindset underpins data analysis for the interpretation of the human genome from basic to clinical research.

How science will help us move forward in 2021.

In 2021, the genetics and genomics community needs to communicate to policymakers how the field of human genetics and genomics is transforming biomedical research and medicine, including its essential role in combatting COVID-19. This is important for ensuring that policies enable a thriving scientific enterprise and provide resources for research advances.

2020 ASHG presidential address: the 'BIG TENT' of genetics/genomics and our world.

This article is based on the address given by the author at the 2020 virtual meeting of the American Society of Human Genetics (ASHG) on October 26, 2020. The video of the original address can be found at the ASHG website.

2020 William Allan Award address: genetics as a way of thinking-cultural inheritance from our teachers.

This article is based on the address given by the author at the 2020 virtual meeting of The American Society of Human Genetics (ASHG) on October 26, 2020. The video of the original address can be found at the ASHG website.

ASHG 2020 Curt Stern Award introduction: Fowzan Sami Alkuraya.

This article is based on the address given by the author at the 2020 virtual meeting of the American Society of Human Genetics (ASHG) on October 26, 2020. The video of the original address can be found at the ASHG website.

2020 Curt Stern Award address: a more perfect clinical genome-how consanguineous populations contribute to the medical annotation of the human genome.

This article is based on the address given by the author at the 2020 virtual meeting of the American Society of Human Genetics (ASHG) on October 26, 2020. The video of the original address can be found at the ASHG website.

Origins of human genetics. A personal perspective.

Genetics evolved as a field of science after 1900 with new theories being derived from experiments obtained in fruit flies, bacteria, and viruses. This personal account suggests that the origins of human genetics can best be traced to the years 1949 to 1959. Several genetic scientific advances in genetics in 1949 yielded results directly relating to humans for the first time, except for a few earlier observations. In 1949 the first textbook of human genetics was published, the American Journal of Human Genetics was founded, and in the previous year the American Society of Human Genetics. In 1940 in Britain a textbook entitled Introduction to Medical Genetics served as a foundation for introducing genetic aspects into medicine. The introduction of new methods for analyzing chromosomes and new biochemical assays using cultured cells in 1959 and subsequent years revealed that many human diseases, including cancer, have genetic causes. It became possible to arrive at a precise cause-related genetic diagnosis. As a result the risk of occurrence or re-occurrence of a disease within a family could be assessed correctly. Genetic counseling as a new concept became a basis for improved patient care. Taken together the advances in medically orientated genetic research and patient care since 1949 have resulted in human genetics being both, a basic medical and a basic biological science. Prior to 1949 genetics was not generally viewed in a medical context. Although monogenic human diseases were recognized in 1902, their occurrence and distribution were considered mainly at the population level.

Disruptive Synergy: Melding of Human Genetics and Clinical Assisted Reproduction.

The melding of human genetics with clinical assisted reproduction, now all but self-evident, gave flight to diagnostic and therapeutic approaches previously deemed infeasible. Preimplantation genetic diagnosis, mitochondrial replacement techniques, and remedial germline editing are particularly noteworthy. Here we explore the relevant disruption brought forth by coalescence of these mutually enabling disciplines with the regulatory and legal implications thereof.

Genetics-Related Activities in Everyday Practice of Family Physicians in Slovenia.

INTRODUCTION: Development of genomic technologies has an important impact on patient management in medicine. Nevertheless, translation of new advances of genomic medicine in primary care is challenging and needs to be adapted to the needs of health systems. OBJECTIVE: The objective of this study was to analyze the current state of the use and the level of confidence in genetic management activities in everyday clinical practice of family practitioners (FPs) in Slovenia. METHODS: We used a cross-sectional observational study design. The dataset was obtained through a questionnaire containing demographics, questions about the use of genetics in everyday practice, and a scale for measuring the responders' confidence in their ability to carry out basic genetic activities during patient treatment. The questionnaire was sent by regular mail to every FP in Slovenia (N = 950). RESULTS: The questionnaire was completed by a total of 271 physicians (response rate 28.5%), with an average physicians' age of 45.5 ± 10.6 years. In their everyday clinical practice, the majority of Slovenian FPs report to encounter genetic conditions more than once a month (241, 91.2%). Family medical history is the most commonly used among all activities related to genetic management of patients. Only 5.9% of Slovenian FPs are confident in their ability to carry out basic activities related to genetic patient management. Most of them believe they are only competent enough to obtain family medical history and identify a positive family history. The FPs who reported a lower degree of confidence are those with the lowest level of education in the field of medical genetics and older physicians (age >50 years). CONCLUSIONS: Slovenian family physicians commonly encounter patients with genetic conditions but are not confident in their ability to carry out basic medical genetic tasks. Therefore, additional education is necessary.

Copy number alterations involving 59 ACMG-recommended secondary findings genes.

In clinical exome/genome sequencing, the American College of Medical Genetics and Genomics (ACMG) recommends reporting of secondary findings unrelated to a patient's phenotype when pathogenic single-nucleotide variants (SNVs) are observed in one of 59 genes associated with a life-threatening, medically actionable condition. Little is known about the incidence and sensitivity of chromosomal microarray analysis (CMA) for detection of pathogenic copy number variants (CNVs) comprising medically-actionable genes. Clinical CMA has been performed on 8865 individuals referred for molecular cytogenetic testing. We retrospectively reviewed the CMA results to identify patients with CNVs comprising genes included in the 59-ACMG list of secondary findings. We evaluated the clinical significance of these CNVs in respect to pathogenicity, phenotypic manifestations, and heritability. We identified 23 patients (0.26%) with relevant CNV either deletions comprising the entire gene or intragenic alterations involving one or more secondary findings genes. A number of patients and/or their family members with pathogenic CNVs manifest or expected to develop an anticipated clinical phenotype and would benefit from preventive management similar to the patients with pathogenic SNVs. To improve patients' care standardization should apply to reporting of both sequencing and CNVs obtained via clinical genome-wide analysis, including chromosomal microarray and exome/genome sequencing.