Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3.

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

Attitudes of genetics professionals toward the return of incidental results from exome and whole-genome sequencing.

Professional recommendations for the return of results from exome and whole-genome sequencing (ES/WGS) have been controversial. The lack of clear guidance about whether and, if so, how to return ES/WGS incidental results limits the extent to which individuals and families might benefit from ES/WGS. The perspectives of genetics professionals, particularly those at the forefront of using ES/WGS in clinics, are largely unknown. Data on stakeholder perspectives could help clarify how to weigh expert positions and recommendations. We conducted an online survey of 9,857 genetics professionals to learn their attitudes on the return of incidental results from ES/WGS and the recent American College of Medical Genetic and Genomics Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. Of the 847 respondents, 760 completed the survey. The overwhelming majority of respondents thought that incidental ES/WGS results should be offered to adult patients (85%), healthy adults (75%), and the parents of a child with a medical condition (74%). The majority thought that incidental results about adult-onset conditions (62%) and carrier status (62%) should be offered to the parents of a child with a medical condition. About half thought that offered results should not be limited to those deemed clinically actionable. The vast majority (81%) thought that individual preferences should guide return. Genetics professionals' perspectives on the return of ES/WGS results differed substantially from current recommendations, underscoring the need to establish clear purpose for recommendations on the return of incidental ES/WGS results as professional societies grapple with developing and updating recommendations.

Anthropologists' views on race, ancestry, and genetics.

Controversies over race conceptualizations have been ongoing for centuries and have been shaped, in part, by anthropologists. OBJECTIVE: To assess anthropologists' views on race, genetics, and ancestry. METHODS: In 2012 a broad national survey of anthropologists examined prevailing views on race, ancestry, and genetics. RESULTS: Results demonstrate consensus that there are no human biological races and recognition that race exists as lived social experiences that can have important effects on health. DISCUSSION: Racial privilege affects anthropologists' views on race, underscoring the importance that anthropologists be vigilant of biases in the profession and practice. Anthropologists must mitigate racial biases in society wherever they might be lurking and quash any sociopolitical attempts to normalize or promote racist rhetoric, sentiment, and behavior.

A content analysis of the views of genetics professionals on race, ancestry, and genetics.

Over the past decade, the proliferation of genetic studies on human health and disease has reinvigorated debates about the appropriate role of race and ancestry in research and clinical care. Here we report on the responses of genetics professionals to a survey about their views on race, genetics, and ancestry across the domains of science, medicine, and society. Through a qualitative content analysis of free-text comments from 515 survey respondents, we identified key themes pertaining to multiple meanings of race, the use of race as a proxy for genetic ancestry, and the relevance of race and ancestry to health. Our findings suggest that for many genetics professionals the questions of what race is and what race means remain both professionally and personally contentious. Looking ahead as genomics is translated into the practice of precision medicine and as learning health care systems offer continued improvements in care through integrated research, we argue for nuanced considerations of both race and genetic ancestry across research and care settings.

A Qualitative Analysis of How Anthropologists Interpret the Race Construct.

This article assesses anthropological thinking about the race concept and its applications. Drawn from a broader national survey of geneticists' and anthropologists' views on race, in this analysis, we provide a qualitative account of anthropologists' perspectives. We delve deeper than simply asserting that "race is a social construct." Instead, we explore the differential ways in which anthropologists describe and interpret how race is constructed. Utilizing the heuristic of constructors, shifters, and reconcilers, we also illustrate the ways in which anthropologists conceptualize their interpretations of race along a broad spectrum as well as what these differential approaches reveal about the ideological and biological consequences of socially defined races, such as racism in general and racialized health disparities in particular. [race concept, social construction, racism, health disparities].

Este artículo evalúa el pensamiento antropológico acerca del concepto de raza y sus aplicaciones. Derivado de una encuesta nacional más amplia de las opiniones de genetistas y antropólogos sobre la raza, en este análisis proveemos un reporte cualitativo, de las perspectivas de los antropólogos. Ahondamos más que simplemente afirmar que "la raza es un constructo social". En cambio, exploramos las formas diferenciales en que los antropólogos describen e interpretan cómo la raza es construida. Utilizando la heurística de constructores, desplazadores, y reconciliadores, también ilustramos las maneras en las que los antropólogos conceptualizan sus interpretaciones de la raza a lo largo de un amplio espectro, y lo que estas aproximaciones diferenciales revelan acerca de las consecuencias ideológicas y biológicas de las razas definidas socialmente, tales como racismo, en general, y las disparidades racializadas en salud, en particular. [concepto de raza, construcción social, racismo, disparidades de salud].