Whole genome sequencing: a considered approach to clinical implementation.
ABSTRACT The recent entry of "whole" exome/"whole" genome sequencing into limited clinical practice has led to a progression of the availability of genome-scale testing beyond deletion/duplication copy number arrays. This unit provides a considered approach to the implementation of such testing in routine clinical practice. Specifically, we will highlight the challenges in patient selection and consent, and the technical issues surrounding test interpretation and reporting. The unit will then provide practical solutions that allow for genome-wide sequencing to be implemented in current clinical practice. Curr. Protoc. Hum. Genet. 77:9.22.1-9.22.7. © 2013 by John Wiley & Sons, Inc.
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ABSTRACT: What's already known about this topic? Incidental findings can occur in many areas of diagnostic testing.Incidental findings, including those of uncertain significance, have many complicated aspects or prenatal diagnosis and are not limited to genetic testing.Whereas guidelines for which findings should be reported and how to report them are being developed in the pediatric and adult genetic testing, little to no guidance exists for prenatal diagnosis.Prenatal Diagnosis 01/2014; 34(1). DOI:10.1002/pd.4275 · 2.51 Impact Factor
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ABSTRACT: Growth evaluations are among the most common referrals to pediatric endocrinologists. Although a number of pathologies, both primary endocrine and non-endocrine, can present with short stature, an estimated 80% of evaluations fail to identify a clear etiology, leaving a default designation of idiopathic short stature (ISS). As a group, several features among children with ISS are suggestive of pathophysiology of the GH-IGF-1 axis, including low serum levels of IGF-1 despite normal GH secretion. Candidate gene analysis of rare cases has demonstrated that severe mutations of genes of the GH-IGF-1 axis can present with a profound height phenotype, leading to speculation that a collection of mild mutations or polymorphisms of these genes can explain poor growth in a larger proportion of patients. Recent genome-wide association studies have identified ~180 genomic loci associated with height that together account for approximately 10% of height variation. With only modest representation of the GH-IGF-1 axis, there is little support for the long-held hypothesis that common genetic variants of the hormone pathway provide the molecular mechanism for poor growth in a substantial proportion of individuals. The height-associated common variants are not observed in the anticipated frequency in the shortest individuals, suggesting rare genetic factors with large effect are more plausible in this group. As we advance towards establishing a molecular mechanism for poor growth in a greater percentage of those currently labeled ISS, we highlight two strategies that will likely be offered with increasing frequency: (1) unbiased genetic technologies including array analysis for copy number variation and whole exome/genome sequencing and (2) epigenetic alterations of key genomic loci. Ultimately data from subsets with similar molecular etiologies may emerge that will allow tailored interventions to achieve the best clinical outcome.International Journal of Pediatric Endocrinology 11/2013; 2013(1):19. DOI:10.1186/1687-9856-2013-19