Web-based tool helps consumers weigh genetic testing for Alzheimer disease

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People dealing with the repercussions of an Alzheimer disease (AD) diagnosis in their family often wonder about their own risk of developing the disease. The ready availability of genetic testing for the e4 allele of the apo-lipoprotein E gene (APOE), an acknowledged risk factor for AD, presents a tempting opportunity to those concerned individuals. But without proper genetic counseling prior to testing, any genetic test result can provoke undue distress and lead to profound misinterpretations. Professional medical societies have recommended against APOE testing because, although the presence of the e4 allele does increase risk, many who carry it never develop the disease. Conversely, others who don't carry the allele do develop the disease. In this issue, a research team from Virginia Tech Carilion School of Medicine, Roanoke, Virginia, presents validation of a new Web-based decision tool designed to assist those considering genetic testing for AD. The tool had been endorsed by focus groups and a panel of medical and genetic professionals but had not undergone field testing. Participants were re-cruited via AD support groups, state agencies, and medical centers. A total of 1,262 individuals viewed the educa-tional material and completed a survey. The vast majority self-identified as white women. Most (81%) had someone in the family who had been diagnosed with AD, and half were themselves caregivers. Nearly all participants (94%) found the tool very helpful or somewhat helpful. But for those who reported not knowing what to expect or who mistakenly believed that APOE testing would provide a definitive diagnosis, the tool seemed most helpful. After using the decision tool, most people in this subset understood that the test would reveal only whether their risk is higher than average. In addition, more than half of participants changed their minds about pursuing genetic testing for AD after using the decision tool. About one-third reported being more likely to take the test, while 20% reported being less likely. The research group has made the decision tool freely available on a dedicated website: http://genetestornot.org. –Karyn Hede, News Editor

Exome-based genomic screening closer to becoming a first-line diagnostic test

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Using an exome- or genome-wide approach, a single test can now detect both single-nucleotide variants (SNVs) and copy-number variants (CNVs). However, most clinical genetic testing still focuses on sequencing targeted panels of genes to detect variation at the nucleotide level while detecting CNVs through an independent platform. In part, this is due to well-documented variability in CNV detection by genome-scale sequencing approaches, depending on the robustness of the algorithms used, as well as variability in false-negative and false-positive rates. Now, a large study from the Netherlands reveals that combining SNV and CNV detection makes exome sequencing suitable as a first-tier diagnostic test. The research team used exome-based CNV testing in 2,603 people affected by a wide range of disorders, including neurodevelopmental disorders, congenital abnormalities, blindness, deafness, and hereditary cancers. Using a two-tiered approach, the researchers first identified rare deletions and duplication events affecting one or more disease genes relevant to each patient's disorder. Second, they conducted an exome-wide analysis that revealed an average of six CNVs per patient. More than 100 patients harbored clinically relevant CNVs. Additionally, a conclusive diagnosis could be made in 51 patients, based on a validated pathogenic CNV combined with an inheritance pattern that matched the clinical phenotype. For another 45 patients, a CNV affected a recessive gene matching the clinical phenotype but no second mutation could be found to enable a diagnosis. In another dozen patients, the identified CNV occurred in a gene for a disorder under investigation. The results revealed that large CNVs can play an important role in many genetic disorders beyond the well-documented neurodevelopmental disorders and perhaps should become an integral part of first-line genetic screening. –Karyn Hede, News Editor