Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing

Abstract

involves karyotyping, whereas in the Netherlands, patients who undergo amniocentesis have a more limited assessment only for trisomies 13, 18, and 21 and the sex chromosomes; thus, the tradeoff is a bit different.In addition, cfDNA is provided as a screening test for trisomies 13, 18, and 21, not just for Down syndrome. However, the performance characteristics of cfDNA for trisomies 13 and 18 are not as favorable as for T21, with a higher rate of falsenegative and false-positive results. In addition, a percentage of patients-somewhere between 1.5% and 8%-fail to obtain a result, usually because of insufficient fetal DNA. Such "low fetal fraction" is associated with obesity, which is a significant problem affecting a high percentage of reproductive-aged women in the United States. It is estimated that 20% to 50% of cfDNA tests fail to provide adequate fetal DNA in obese women. In addition, low fetal fraction is also associated with aneuploidy; therefore, women with cfDNA test failure should be considered high risk and offered follow-up with diagnostic testing (as well as a second attempt at cfDNA). When these potential outcomes are all considered, the performance characteristics of cfDNA versus traditional screening are not as clearly superior.Like the authors of this abstracted paper, several other authors and experts (Prenat Diagn 2013;33 (7):636-642) have suggested a contingent approach, using multiple marker screening as an initial screening tool, and then offering NIPT to intermediate-risk patients and either cfDNA or invasive testing to the highest-risk patients. Before completely changing the current standard of care, we need to understand this tradeoff. These authors consider comparative costs, but do not really provide incremental cost-effectiveness ratios, which are the best way to compare these strategies. While cfDNA is a better test if we are looking at a very precise test for a single disorder, only in patients in whom the test is successful at providing a result current screening may be preferable if we are looking to screen the entire population for a broad range of birth defects. Cost utility analyses, conducted by independent investigators and considering all important outcomes, are clearly needed before our approach completely changes. -MEN)

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole‐exome sequencing

“…1 While originally used almost exclusively for novel gene discovery, 2,3 WES is now routinely considered the approach of choice for the medical geneticists' most clinically challenging rare disease patients. [4][5][6][7][8][9] The diagnostic yield following clinical WES varies considerably; large cohorts have shown that the genetic basis of disease will be identified in 20%-60% of patients. [4][5][6][7][8][9][10] For those who receive a molecular diagnosis, not only does the diagnostic odyssey come to an end but also appropriate genetic counseling for family members becomes available, and in some cases disease management is tailored based on knowledge of the natural history of the disease.…”

“…[4][5][6][7][8][9] The diagnostic yield following clinical WES varies considerably; large cohorts have shown that the genetic basis of disease will be identified in 20%-60% of patients. [4][5][6][7][8][9][10] For those who receive a molecular diagnosis, not only does the diagnostic odyssey come to an end but also appropriate genetic counseling for family members becomes available, and in some cases disease management is tailored based on knowledge of the natural history of the disease. 1,11 The process of arriving at a molecular diagnosis in the "solved" group of patients is not without its challenges.…”

“…Moreover, the hypothesis-free nature of WES has provided a distinct advantage in the diagnosis of such clinically challenging patients. Thus, it is not surprising that patients with multiple genetic diseases are being increasingly mentioned either as single case reports [13][14][15] or within larger cohorts, [4][5][6][7][8][9][10]16 as WES becomes increasingly available in the Medical Genetics clinic. Existing literature on multiple genetic diseases focuses on the identification of this phenomenon in single affected individuals ascertained through clinical WES.…”

Are physicians prepared for whole genome sequencing? a qualitative analysis

“…fax: +617 264 8795; e-mail: kchristensen@ genetics.med.harvard.edu Received 23 March 2015, revised and accepted for publication 15 June 2015 Whole genome sequencing (WGS) may soon play an important role in primary and specialty care. Falling technical costs and turnaround time are making widespread WGS use feasible (1)(2)(3)(4), and it is already useful for diagnosing disease, informing treatment decisions, and assisting life decisions (1,(5)(6)(7)(8). Genomic sequencing is a key component of President Obama's Precision Medicine Initiative (9), and healthcare systems are developing the infrastructure to enhance the utility of genomics (10,11).…”

Practical considerations in the clinical application of whole‐exome sequencing

“…Until recently, the reports of WES in Mendelian diseases were from research studies or case series (7,(9)(10)(11)(12)(13)(14). Three clinical laboratories performing WES on a clinical basis have reported a molecular diagnostic rate of 25-30% (3,5,15,16). Although these reports are important contributions on the molecular diagnostic rate of WES, they do not examine the clinical relevance of the molecular findings on the remaining 75%, or if the clinicians concurred with the laboratory's interpretation (3,5).…”