<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Posey, Jennifer E</style></author><author><style face="normal" font="default" size="100%">O'Donnell-Luria, Anne H</style></author><author><style face="normal" font="default" size="100%">Chong, Jessica X</style></author><author><style face="normal" font="default" size="100%">Harel, Tamar</style></author><author><style face="normal" font="default" size="100%">Jhangiani, Shalini N</style></author><author><style face="normal" font="default" size="100%">Coban Akdemir, Zeynep H</style></author><author><style face="normal" font="default" size="100%">Buyske, Steven</style></author><author><style face="normal" font="default" size="100%">Pehlivan, Davut</style></author><author><style face="normal" font="default" size="100%">Carvalho, Claudia M B</style></author><author><style face="normal" font="default" size="100%">Baxter, Samantha</style></author><author><style face="normal" font="default" size="100%">Sobreira, Nara</style></author><author><style face="normal" font="default" size="100%">Liu, Pengfei</style></author><author><style face="normal" font="default" size="100%">Wu, Nan</style></author><author><style face="normal" font="default" size="100%">Rosenfeld, Jill A</style></author><author><style face="normal" font="default" size="100%">Kumar, Sushant</style></author><author><style face="normal" font="default" size="100%">Avramopoulos, Dimitri</style></author><author><style face="normal" font="default" size="100%">White, Janson J</style></author><author><style face="normal" font="default" size="100%">Doheny, Kimberly F</style></author><author><style face="normal" font="default" size="100%">Witmer, P Dane</style></author><author><style face="normal" font="default" size="100%">Boehm, Corinne</style></author><author><style face="normal" font="default" size="100%">Sutton, V Reid</style></author><author><style face="normal" font="default" size="100%">Muzny, Donna M</style></author><author><style face="normal" font="default" size="100%">Boerwinkle, Eric</style></author><author><style face="normal" font="default" size="100%">Günel, Murat</style></author><author><style face="normal" font="default" size="100%">Nickerson, Deborah A</style></author><author><style face="normal" font="default" size="100%">Mane, Shrikant</style></author><author><style face="normal" font="default" size="100%">MacArthur, Daniel G</style></author><author><style face="normal" font="default" size="100%">Gibbs, Richard A</style></author><author><style face="normal" font="default" size="100%">Hamosh, Ada</style></author><author><style face="normal" font="default" size="100%">Lifton, Richard P</style></author><author><style face="normal" font="default" size="100%">Matise, Tara C</style></author><author><style face="normal" font="default" size="100%">Rehm, Heidi L</style></author><author><style face="normal" font="default" size="100%">Gerstein, Mark</style></author><author><style face="normal" font="default" size="100%">Bamshad, Michael J</style></author><author><style face="normal" font="default" size="100%">Valle, David</style></author><author><style face="normal" font="default" size="100%">Lupski, James R</style></author></authors><translated-authors><author><style face="normal" font="default" size="100%">Centers for Mendelian Genomics</style></author></translated-authors></contributors><titles><title><style face="normal" font="default" size="100%">Insights into genetics, human biology and disease gleaned from family based genomic studies.</style></title><secondary-title><style face="normal" font="default" size="100%">Genet Med</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Genet. Med.</style></alt-title></titles><dates><year><style  face="normal" font="default" size="100%">2019</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2019 04</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">21</style></volume><pages><style face="normal" font="default" size="100%">798-812</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of &gt;75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel &quot;disease gene&quot; discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">4</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/30655598?dopt=Abstract</style></custom1></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Posey, Jennifer E</style></author><author><style face="normal" font="default" size="100%">Harel, Tamar</style></author><author><style face="normal" font="default" size="100%">Liu, Pengfei</style></author><author><style face="normal" font="default" size="100%">Rosenfeld, Jill A</style></author><author><style face="normal" font="default" size="100%">James, Regis A</style></author><author><style face="normal" font="default" size="100%">Coban Akdemir, Zeynep H</style></author><author><style face="normal" font="default" size="100%">Walkiewicz, Magdalena</style></author><author><style face="normal" font="default" size="100%">Bi, Weimin</style></author><author><style face="normal" font="default" size="100%">Xiao, Rui</style></author><author><style face="normal" font="default" size="100%">Ding, Yan</style></author><author><style face="normal" font="default" size="100%">Xia, Fan</style></author><author><style face="normal" font="default" size="100%">Beaudet, Arthur L</style></author><author><style face="normal" font="default" size="100%">Muzny, Donna M</style></author><author><style face="normal" font="default" size="100%">Gibbs, Richard A</style></author><author><style face="normal" font="default" size="100%">Boerwinkle, Eric</style></author><author><style face="normal" font="default" size="100%">Eng, Christine M</style></author><author><style face="normal" font="default" size="100%">Sutton, V Reid</style></author><author><style face="normal" font="default" size="100%">Shaw, Chad A</style></author><author><style face="normal" font="default" size="100%">Plon, Sharon E</style></author><author><style face="normal" font="default" size="100%">Yang, Yaping</style></author><author><style face="normal" font="default" size="100%">Lupski, James R</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.</style></title><secondary-title><style face="normal" font="default" size="100%">N Engl J Med</style></secondary-title><alt-title><style face="normal" font="default" size="100%">N Engl J Med</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Exome</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Diseases, Inborn</style></keyword><keyword><style  face="normal" font="default" size="100%">Genetic Variation</style></keyword><keyword><style  face="normal" font="default" size="100%">Genotyping Techniques</style></keyword><keyword><style  face="normal" font="default" size="100%">High-Throughput Nucleotide Sequencing</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Phenotype</style></keyword><keyword><style  face="normal" font="default" size="100%">Retrospective Studies</style></keyword><keyword><style  face="normal" font="default" size="100%">Sequence Analysis, DNA</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2017</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2017 Jan 05</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">376</style></volume><pages><style face="normal" font="default" size="100%">21-31</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;b&gt;BACKGROUND: &lt;/b&gt;Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes.&lt;/p&gt;&lt;p&gt;&lt;b&gt;METHODS: &lt;/b&gt;We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology.&lt;/p&gt;&lt;p&gt;&lt;b&gt;RESULTS: &lt;/b&gt;A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77×10).&lt;/p&gt;&lt;p&gt;&lt;b&gt;CONCLUSIONS: &lt;/b&gt;In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).&lt;/p&gt;</style></abstract><issue><style face="normal" font="default" size="100%">1</style></issue><custom1><style face="normal" font="default" size="100%">https://www.ncbi.nlm.nih.gov/pubmed/27959697?dopt=Abstract</style></custom1></record></records></xml>