Mobilizing Mutations

Abstract

In his book, MobilizingMutations: Human Genetics in the Age of Patient Advocacy, Daniel Navon, of University of California, San Diego, gives a thought-provoking sociological analysis of the history of medical genetics from the beginning to this date, examining the impact of genetics-based diagnosis on individuals, families, advocacy organizations, and the society. His aim is to apply qualitative biomedical research “to examine the conditions, organizations, and people who exemplify genomic designation.” The focus of this 384-page book, which is divided into an introduction, 8 chapters, each with its own conclusion, and a summarizing conclusion, is the emergence of genomically designated conditions representing the nexus between medical genetics and sociology. Genomic designation is classifying disease based on genetic mutations rather than by clinical symptoms. Today, the vast majority of inherited conditions are defined by symptom-based diagnostic criteria, even though a significant number of the condition-associated mutations have been identified. By contrast, in genomic designation, the only criterion for diagnosis is the presence of a particular genetic mutation. This approach defines pathological syndromes by genomic analysis de novo. The author, using examples of psychiatric conditions, demonstrates how disease categories can be “lumped together, split up, or recalibrated” based on genomic designation. Navon argues that while early genetics findings had little impact on clinical practice, mutations linked to genomically designated conditions have become powerful factors because of their “social mobilization,” starting from networks of medical professionals and patient support and advocacy groups, and up to the creation of registered foundations, and to the attraction of public and private funding for the research. Moreover, genomically designated conditions create frameworks to attract biomedical researchers and pharmaceutical companies working on biological models that can help to decipher the pathophysiology of more common genetically complex medical conditions. As of 2017, there were more than 20 genomically designated conditions with established advocacy organizations. Most of these inherited conditions are the result of chromosomal abnormalities, such as aneuploidies, microdeletions, and duplications, with only a few linked to point mutations. Many more novel genetic syndromes have been reported within the past several years, and some of them are becoming a focus of effective social mobilization and community formation, such as mechanistic target of rapamycin kinase gene (MTOR) mutations (Smith-Kingsmore syndrome). However, an important issue is that a genomically designated condition is open to encompassing a vast range of phenotypic variations present in the mutation carriers; it can include not only mutation-associated disease phenotypes, but also subclinical traits in some of the healthy carriers, thus blurring the boundary between illness and health. Incomplete penetrance as an all-or-none diagnostic approach should be replaced by continuums of impairment variation. Endophenotyping (observation of nuanced signs of difference observed in significant proportion of people with a particular genetic mutation) allows normalizing pathological findings because “a finding that is pathological in the general population may be part of the normal development trajectory for people with a particular mutation.” In the postgenomic era, next-generation sequencing technologies have made feasible a diagnosis based on patients’ whole-exome (WES) or whole-genome (WGS) sequencing findings; publicly available databases such as OMIM, DECIPHER, ClinVar, ExAc, and others allow rapid bioinformatics evaluation of the newly identified mutations. Social media and other communication technologies drastically accelerate the formation of novel mutation-based groups of patients (ie, emergence of novel genetically designation conditions). It is noteworthy that only a small minority of these novel conditions have been mobilized yet. The author argues that the future of genomically designated conditions remains uncertain because of several factors, the main of which is an increasing availability of noninvasive prenatal genetic screening (NIPT), resulting in lower prevalence of genetic disorders in the future. He writes that “the specter of eugenics is a serious cause of concern” in relation to genomically designated mutations, most of which are now included in NIPT kits. Navon mentions some other debatable issues, such as the potential for iatrogenic harm, self-fulfilling prophecies for mutation carriers, a prospect of a higher ratio of genetic disorders in socioeconomically disadvantaged populations, and an ethical issue of seeing mildly affected people as patients of a genetic disorder. In summary, the book is well organized and written in a clear and straightforward language, presenting a novel perspective in perception of genetic disorders. It will be equally interesting to social scientists and medical professionals and to a diverse audience, including those whose lives are affected by a genetic disorder, who are interested in medical genetics, or who are involved with biomedical and social issues related to genetic disorders. Sheila Riazi, MSc, MDNatalia Kraeva, PhDDepartment of Anesthesia and Pain ManagementUniversity Health NetworkUniversity of TorontoOntario, Canada[email protected]