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Health See other Health Articles Title: Loss of Function Mutations Affect 1 in 30 Healthy Individuals Medscape... NEW YORK (Reuters Health) - About 3% of apparently healthy individuals harbor loss of function (LOF) mutations associated with recognizable phenotypes in themselves or their families, according to results from 951 participants from the ClinSeq study, a large-scale genome sequencing pilot study. "These data show that we can begin to imagine what predictive genomic or precision medicine could look like," Dr. Leslie G. Biesecker, from the National Human Genome Research Institute, Bethesda, Maryland, told Reuters Health by email. "We have taken a subset of genes and a subset of mutations in such genes and identified that 3% of an apparently healthy group had identifiable genetic disorders." "Were we to expand this to all human disease genes and all genetic disorders, it should be much higher. This means that while each of these disorders is rare, in aggregate, they are present in a lot of people," he said. To arrive at these results, Dr. Biesecker's team focused on LOF variants for which there was evidence that it could cause disease and then evaluated participants with these variants to identify phenotypic characteristics in them or their close family members that could be attributable to the LOF variant. Among the 951 participants, they identified 103 (11.1%) with a rare, heterogeneous LOF variant in a gene that can actually cause disease via loss-of-function alleles. After adjustment for ascertainment biases, they determined that 28 of these LOF variants were associated with positive phenotypes in the individual or a close family member, according to the June 4 online report in the American Journal of Human Genetics. "Although it is true that not all of the phenotypes detected here are medically actionable, this study serves as a proof of principle that there might indeed be predictive value in healthy genomes and exomes, once our mutation prediction algorithms improve and broaden to encompass all genes and many mutations," the researchers conclude. "We should start to question the model that the only people who get exome sequencing (or any gene test for that matter) are those who are already known to suffer from genetic disease or who have had multiple family members suffer or die from genetic disease," Dr. Biesecker said. "We should start to envision changing to an approach where we look at the genome before people suffer and die to find diseases when we have a better chance to prevent them or limit the morbidity they cause." "Exome sequencing is not magic, and we have a good deal of work to do before it is routine," he explained. "But thousands of people are having such testing each year for rare or unexplained disease, or to help with cancer treatment. Physicians outside of academic centers are increasingly likely to encounter patients who have been sequenced and they will need to develop skills for managing patients using results from this testing. We have been saying for years that genomics is coming to medicine - it is here." Dr. Biesecker added, "Currently, clinical exome sequencing costs in the range of $4-5,000 and genome sequencing $8-12,000, so it is very expensive. At today's prices, it is just too expensive for routine use, and insurers would be unlikely to reimburse for it." The National Institutes of Health supported this research. One coauthor reported receiving royalties from Genentech, and two coauthors reported receiving licensing funding from BIOBASE/Qiagen. SOURCE: http://bit.ly/1dPX9VV Am J Human Genetics 2015. Poster Comment: exome The sum total of the exons in a genome, which comprise about 1% of human DNA. The exome is regarded as the most functionally relevant DNA, as it encodes proteins and gene ex·on (k′sOn) n. A nucleotide sequence in DNA that carries the code for the final mRNA molecule and thus defines a protein's amino acid sequence. Also called coding sequence. exon regions of a primary RNA transcript in eukaryotic cells that are coding and are joined together when introns are spliced-out, to make the functional mRNA. in·tron (-n′trOn) n. A segment of a gene situated between exons that is removed before translation of messenger RNA and does not function in coding for protein synthesis. Post Comment Private Reply Ignore Thread
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