The ACMG guidelines on the return of secondary findings is a very conservative set of recommendations. They state that they are attempting “to strike a balance between the positions of genetic libertarians and the genetic empiricists, guided by the currently available scientific literature, clinical experience, the consensus of our Working Group members and the traditions of clinical medicine.”
But, this report is biased heavily in favor of the genetic empiricists, as they are suggesting that results be returned for ~56 genes, out of an approximate total of ~20,000 protein-coding genes in the human genome, not to mention the thousands of other identified, important noncoding elements of the genome! There are ~6 billion nucleotides of DNA in every cell of the human body, and there are ~25-100 trillion cells in each human body. Given somatic mosaicism, epigenetic changes, and environmental differences, no two human beings are the same, and therefore the expressivity of any mutation will be different in each person.
Therefore, how we will ever get to a world of millions of whole genomes shared and analyzed for numerous additive, epistatic interactions and gene X environment interactions, so that we can make any reliable predictions for any one human being, if we are only recommending return of results from ~56 genes? We need to sequence and collate the raw data from thousands and then millions of exomes and genomes, so that we can actually begin to really understand the expressivity patterns of any mutation in the human genome in any one person. The report does not even cite any of the revolutionary and disruptive work by genetic libertarians, including that of 23andMe and the Personal Genome Project. Some representative papers are below. This material is also discussed in the review in Genome Medicine that I published last year.
Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing
Uta Francke 1,2, Cheri Dijamco1, Amy K. Kiefer1, Nicholas Eriksson1, Bianca Moiseff1, Joyce Y. Tung1, Joanna L. Mountain1
A public resource facilitating clinical use of genomes.
Ball MP, Thakuria JV, Zaranek AW, Clegg T, Rosenbaum AM, Wu X, Angrist M, Bhak J, Bobe J, Callow MJ, Cano C, Chou MF, Chung WK, Douglas SM, Estep PW, Gore A, Hulick P, Labarga A, Lee JH, Lunshof JE, Kim BC, Kim JI, Li Z, Murray MF, Nilsen GB, Peters BA, Raman AM, Rienhoff HY, Robasky K, Wheeler MT, Vandewege W, Vorhaus DB, Yang JL, Yang L, Aach J, Ashley EA, Drmanac R, Kim SJ, Li JB, Peshkin L, Seidman CE, Seo JS, Zhang K, Rehm HL, Church GM.
Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):11920-7. doi: 10.1073/pnas.1201904109. Epub 2012 Jul 13.
Efficient replication of over 180 genetic associations with self-reported medical data.
Tung JY, Do CB, Hinds DA, Kiefer AK, Macpherson JM, Chowdry AB, Francke U, Naughton BT, Mountain JL, Wojcicki A, Eriksson N.
PLoS One. 2011;6(8):e23473. doi: 10.1371/journal.pone.0023473. Epub 2011 Aug 17.
Comparison of family history and SNPs for predicting risk of complex disease.
Do CB, Hinds DA, Francke U, Eriksson N.
PLoS Genet. 2012;8(10):e1002973. doi: 10.1371/journal.pgen.1002973. Epub 2012 Oct 11.
Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease.
Do CB, Tung JY, Dorfman E, Kiefer AK, Drabant EM, Francke U, Mountain JL, Goldman SM, Tanner CM, Langston JW, Wojcicki A, Eriksson N.
PLoS Genet. 2011 Jun;7(6):e1002141. doi: 10.1371/journal.pgen.1002141. Epub 2011 Jun 23.
Identifying disease mutations in genomic medicine settings: current challenges and how to accelerate progress
Gholson J Lyon and Kai Wang
Genome Medicine 2012, 4:58 doi:10.1186/gm359