Contemplating effects of genomic structural variation

Abstract

Two developments have sparked new directions in the genetics-to-genomics transition for research and medical applications: the advance of whole-genome assays by array or DNA sequencing technologies, and the discovery among human genomes of extensive submicroscopic genomic structural variation, including copy number variation.For health care to benefit from interpretation of genomic data, we need to know how these variants contribute to the phenotype of the individual. Research is revealing the spectrum, both in size and complexity, of structural genotypic variation, and its association with a broad range of human phenotypes. Genomic disorders associated with relatively large, recurrent contiguous variants have been recognized for some time, as have certain Mendelian traits associated with functional disruption of single genes by structural variation. More recent examples from phenotype-and genotype-driven studies demonstrate a greater level of complexity, with evidence of incremental dosage effects, gene interaction networks, buffering and modifiers, and position effects. Mechanisms underlying such variation are emerging to provide a handle on the bulk of human variation, which is associated with complex traits and adaptive potential. Interpreting genotypes for personalized health care and communicating knowledge to the individual will be significant challenges for genomics professionals. Genet Med 2008:10(9):639 -647.

Risk factors for autism: translating genomic discoveries into diagnostics

“…Very large sets of data are needed to establish reproducible links between CNVs or sequence variants and phenotypic elements or patterns. Research can be phenotype-driven-such as when a cohort is deWned by shared characteristics-or genotypedriven, in which groups are clustered according to common genomic variants (Buchanan and Scherer 2008). Dr. Bridget Fernandez described a comprehensive study (unpublished data) of 150 consecutive ASD probands in Newfoundland, Canada, grouped by dysmorphic Wndings into essential or complex ASD or equivocal (Miles et al 2005).…”

What is a meaningful result? Disclosing the results of genomic research in autism to research participants

“…Although these situations are not without challenge, see Miller et al, 21 we focus in this paper on research findings of uncertain clinical significance (eg, susceptibility variants, copy number variants). 22,23 FINDINGS By general consensus, the autism genomics research enterprise was not ready, at the time of our study, to permit routine disclosure of genetic research results to individual participants. Correspondingly, researchers had disclosed few such results and few parents had received them.…”

Challenges for CNV interpretation in clinical molecular karyotyping: Lessons learned from a 1001 sample experience

“…A catalogue of this structural variation is provided by the Database of Genomic Variants (DGV, http://projects.tcag.ca/ variation/) and currently covers about 29% of the human genome. This notion has complicated the interpretation of results, as the clinical significance of these CNVs remains largely unknown [18,19]. Although guidelines for the use of molecular karyotyping in clinical diagnostics have been suggested [20][21][22], the clinical interpretation of detected copy number variants is still challenging.…”