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Biesecker L.G.,Human Genome Research Institutes
Genome Research | Year: 2013

Genomics has profoundly changed biology by scaling data acquisition, which has provided researchers with the opportunity to interrogate biology in novel and creative ways. No longer constrained by low-throughput assays, researchers have developed hypothesis-generating approaches to understand the molecular basis of nature - both normal and pathological. The paradigm of hypothesis-generating research does not replace or undermine hypothesis-testing modes of research; instead, it complements them and has facilitated discoveries that may not have been possible with hypothesistesting research. The hypothesis-generating mode of research has been primarily practiced in basic science but has recently been extended to clinical-translational work as well. Just as in basic science, this approach to research can facilitate insights into human health and disease mechanisms and provide the crucially needed data set of the full spectrum of genotype-phenotype correlations. Finally, the paradigm of hypothesis-generating research is conceptually similar to the underpinning of predictive genomic medicine, which has the potential to shift medicine from a primarily population- or cohort-based activity to one that instead uses individual susceptibility, prognostic, and pharmacogenetic profiles to maximize the efficacy and minimize the iatrogenic effects of medical interventions. © 2013, Published by Cold Spring Harbor Laboratory Press.

Biesecker L.G.,Human Genome Research Institutes
American Journal of Human Genetics | Year: 2013

The topic of incidental variants detected through exome and genome sequencing is controversial, both in clinical practice and in research. The arguments for and against the deliberate analysis and return of incidental variants focus on issues of clinical validity, clinical utility, autonomy, clinical and research infrastructure and costs, and, in the research arena, therapeutic misconception. These topics are briefly reviewed and an argument is made that these variants are the future of genomic medicine. As a field, we should take full advantage of all opportunities to study these variants by searching them out, returning them to patients and research participants, and studying their utility for predictive medicine. © 2013 The American Society of Human Genetics.

Biesecker L.G.,Human Genome Research Institutes | Spinner N.B.,Childrens Hospital of Philadelphia
Nature Reviews Genetics | Year: 2013

Genomic technologies, including next-generation sequencing (NGS) and single-nucleotide polymorphism (SNP) microarrays, have provided unprecedented opportunities to assess genomic variation among, and increasingly within, individuals. It has long been known that cancer is a mosaic genetic disorder, but mosaicism is now apparent in a diverse range of other clinical disorders, as indicated by their tissue distributions and inheritance patterns. Recent technical advances have uncovered the causative mosaic variant underlying many of these conditions and have provided insight into the pervasiveness of mosaicism in normal individuals. Here, we discuss the clinical and molecular classes of mosaicism, their detection and the biological insights gained from these studies. © 2013 Macmillan Publishers Limited. All rights reserved.

Purpose: The debate surrounding the return of results from high-throughput genomic interrogation encompasses many important issues including ethics, law, economics, and social policy. As well, the debate is also informed by the molecular, genetic, and clinical foundations of the emerging field of clinical genomics, which is based on this new technology. This article outlines the main biomedical considerations of sequencing technologies and demonstrates some of the early clinical experiences with the technology to enable the debate to stay focused on real-world practicalities. Methods: These experiences are based on early data from the ClinSeq project, which is a project to pilot the use of massively parallel sequencing in a clinical research context with a major aim to develop modes of returning results to individual subjects. Results: The study has enrolled >900 subjects and generated exome sequence data on 572 subjects. These data are beginning to be interpreted and returned to the subjects, which provides examples of the potential usefulness and pitfalls of clinical genomics. Conclusion: There are numerous genetic results that can be readily derived from a genome including rare, high-penetrance traits, and carrier states. However, much work needs to be done to develop the tools and resources for genomic interpretation. The main lesson learned is that a genome sequence may be better considered as a health-care resource, rather than a test, one that can be interpreted and used over the lifetime of the patient. ©American College of Medical Genetics and Genomics.

Solomon B.D.,Human Genome Research Institutes
Orphanet Journal of Rare Diseases | Year: 2011

VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. In addition to these core component features, patients may also have other congenital anomalies. Although diagnostic criteria vary, the incidence is estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants. The condition is ascertained clinically by the presence of the above-mentioned malformations; importantly, there should be no clinical or laboratory-based evidence for the presence of one of the many similar conditions, as the differential diagnosis is relatively large. This differential diagnosis includes (but is not limited to) Baller-Gerold syndrome, CHARGE syndrome, Currarino syndrome, deletion 22q11.2 syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus. Though there are hints regarding causation, the aetiology has been identified only in a small fraction of patients to date, likely due to factors such as a high degree of clinical and causal heterogeneity, the largely sporadic nature of the disorder, and the presence of many similar conditions. New genetic research methods offer promise that the causes of VACTERL association will be better defined in the relatively near future. Antenatal diagnosis can be challenging, as certain component features can be difficult to ascertain prior to birth. The management of patients with VACTERL/VATER association typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment. © 2011 Solomon; licensee BioMed Central Ltd.

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