000263608 001__ 263608
000263608 005__ 20190619220201.0
000263608 022__ $$a0027-8424
000263608 02470 $$a000455610300037$$2isi
000263608 0247_ $$a10.1073/pnas.1808403116$$2doi
000263608 037__ $$aARTICLE
000263608 245__ $$aBlacklisting variants common in private cohorts but not in public databases optimizes human exome analysis
000263608 260__ $$c2019$$aWashington$$bNATL ACAD SCIENCES
000263608 269__ $$a2019-01-15
000263608 336__ $$aJournal Articles
000263608 520__ $$aComputational analyses of human patient exomes aim to filter out as many nonpathogenic genetic variants (NPVs) as possible, without removing the true disease-causing mutations. This involves comparing the patient's exome with public databases to remove reported variants inconsistent with disease prevalence, mode of inheritance, or clinical penetrance. However, variants frequent in a given exome cohort, but absent or rare in public databases, have also been reported and treated as NPVs, without rigorous exploration. We report the generation of a blacklist of variants frequent within an in-house cohort of 3,104 exomes. This blacklist did not remove known pathogenic mutations from the exomes of 129 patients and decreased the number of NPVs remaining in the 3,104 individual exomes by a median of 62%. We validated this approach by testing three other independent cohorts of 400, 902, and 3,869 exomes. The blacklist generated from any given cohort removed a substantial proportion of NPVs (11-65%). We analyzed the blacklisted variants computationally and experimentally. Most of the blacklisted variants corresponded to false signals generated by incomplete reference genome assembly, location in low-complexity regions, bioinformatic misprocessing, or limitations inherent to cohort-specific private alleles (e.g., due to sequencing kits, and genetic ancestries). Finally, we provide our precalculated blacklists, together with ReFiNE, a program for generating customized blacklists from any medium-sized or large in-house cohort of exome (or other next-generation sequencing) data via a user-friendly public web server. This work demonstrates the power of extracting variant blacklists from private databases as a specific in-house but broadly applicable tool for optimizing exome analysis.
000263608 650__ $$aMultidisciplinary Sciences
000263608 650__ $$aScience & Technology - Other Topics
000263608 6531_ $$aexome
000263608 6531_ $$avariant
000263608 6531_ $$ablacklist
000263608 6531_ $$awes analysis
000263608 6531_ $$awes annotation
000263608 6531_ $$agene mutation database
000263608 6531_ $$agenome
000263608 6531_ $$amononucleotide
000263608 6531_ $$aguidelines
000263608 6531_ $$aframework
000263608 6531_ $$adisease
000263608 6531_ $$aerrors
000263608 700__ $$aMaffucci, Patrick
000263608 700__ $$aBigio, Benedetta
000263608 700__ $$aRapaport, Franck
000263608 700__ $$aCobat, Aurelie
000263608 700__ $$g259362$$0249100$$aBorghesi, Alessandro
000263608 700__ $$aLopez, Marie
000263608 700__ $$aPating, Etienne
000263608 700__ $$aBolze, Alexandre
000263608 700__ $$aShang, Lei
000263608 700__ $$aBendavid, Matthieu
000263608 700__ $$aScott, Eric M.
000263608 700__ $$aStenson, Peter D.
000263608 700__ $$aCunningham-Rundles, Charlotte
000263608 700__ $$aCooper, David N.
000263608 700__ $$aGleeson, Joseph G.
000263608 700__ $$g213497$$0245371$$aFellay, Jacques
000263608 700__ $$aQuintana-Murci, Lluis
000263608 700__ $$aCasanova, Jean-Laurent
000263608 700__ $$aAbel, Laurent
000263608 700__ $$aBoisson, Bertrand
000263608 700__ $$aItan, Yuval
000263608 773__ $$k3$$j116$$q950-959$$tProceedings Of The National Academy Of Sciences Of The United States Of America
000263608 8560_ $$fjacques.fellay@epfl.ch
000263608 909C0 $$yApproved$$pGR-FE$$xU12477$$mjacques.fellay@epfl.ch$$zBlumer, Eliane$$0252395
000263608 909CO $$particle$$ooai:infoscience.epfl.ch:263608$$pSV
000263608 961__ $$afantin.reichler@epfl.ch
000263608 973__ $$aEPFL$$sPUBLISHED$$rREVIEWED
000263608 980__ $$aARTICLE
000263608 980__ $$aWoS
000263608 981__ $$aoverwrite