@article {800, title = {Multi-omic studies on missense PLG variants in families with otitis media.}, journal = {Sci Rep}, volume = {10}, year = {2020}, month = {2020 09 14}, pages = {15035}, abstract = {

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045~T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045~T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

}, keywords = {Animals, Ear, Middle, Female, Genomics, Humans, Male, Mice, Microbiota, Mutation, Missense, Otitis Media, Pedigree, Plasminogen, Polymorphism, Single Nucleotide, Saliva}, issn = {2045-2322}, doi = {10.1038/s41598-020-70498-w}, author = {Bootpetch, Tori C and Hafr{\'e}n, Lena and Elling, Christina L and Baschal, Erin E and Manichaikul, Ani W and Pine, Harold S and Szeremeta, Wasyl and Scholes, Melissa A and Cass, Stephen P and Larson, Eric D and Chan, Kenny H and Ishaq, Rafaqat and Prager, Jeremy D and Shaikh, Rehan S and Gubbels, Samuel P and Yousaf, Ayesha and Wine, Todd M and Bamshad, Michael J and Yoon, Patricia J and Jenkins, Herman A and Nickerson, Deborah A and Streubel, Sven-Olrik and Friedman, Norman R and Frank, Daniel N and Einarsdottir, Elisabet and Kere, Juha and Riazuddin, Saima and Daly, Kathleen A and Leal, Suzanne M and Ryan, Allen F and Mattila, Petri S and Ahmed, Zubair M and Sale, Michele M and Chonmaitree, Tasnee and Santos-Cortez, Regie Lyn P} } @article {595, title = {Insights into genetics, human biology and disease gleaned from family based genomic studies.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 04}, pages = {798-812}, abstract = {

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >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 "disease gene" 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.

}, keywords = {Databases, Genetic, Genetic Diseases, Inborn, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome, Human, Genomics, Humans, National Institutes of Health (U.S.), Pedigree, United States, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-018-0408-7}, author = {Posey, Jennifer E and O{\textquoteright}Donnell-Luria, Anne H and Chong, Jessica X and Harel, Tamar and Jhangiani, Shalini N and Coban Akdemir, Zeynep H and Buyske, Steven and Pehlivan, Davut and Carvalho, Claudia M B and Baxter, Samantha and Sobreira, Nara and Liu, Pengfei and Wu, Nan and Rosenfeld, Jill A and Kumar, Sushant and Avramopoulos, Dimitri and White, Janson J and Doheny, Kimberly F and Witmer, P Dane and Boehm, Corinne and Sutton, V Reid and Muzny, Donna M and Boerwinkle, Eric and G{\"u}nel, Murat and Nickerson, Deborah A and Mane, Shrikant and MacArthur, Daniel G and Gibbs, Richard A and Hamosh, Ada and Lifton, Richard P and Matise, Tara C and Rehm, Heidi L and Gerstein, Mark and Bamshad, Michael J and Valle, David and Lupski, James R} } @article {22, title = {My46: a Web-based tool for self-guided management of genomic test results in research and clinical settings.}, journal = {Genet Med}, volume = {19}, year = {2017}, month = {2017 Apr}, pages = {467-475}, abstract = {

A major challenge to implementing precision medicine is the need for an efficient and cost-effective strategy for returning individual genomic test results that is easily scalable and can be incorporated into multiple models of clinical practice. My46 is a Web-based tool for managing the return of genetic results that was designed and developed to support a wide range of approaches to disclosing results, ranging from traditional face-to-face disclosure to self-guided models. My46 has five key functions: set and modify results-return preferences, return results, educate, manage the return of results, and assess the return of results. These key functions are supported by six distinct modules and a suite of features that enhance the user experience, ease site navigation, facilitate knowledge sharing, and enable results-return tracking. My46 is a potentially effective solution for returning results and supports current trends toward shared decision making between patients and providers and patient-driven health management.Genet Med 19 4, 467-475.

}, keywords = {Biomedical Research, Computational Biology, Decision Making, Genomics, Humans, Internet, Medical Informatics, Patient Access to Records, Precision Medicine}, issn = {1530-0366}, doi = {10.1038/gim.2016.133}, author = {Tabor, Holly K and Jamal, Seema M and Yu, Joon-Ho and Crouch, Julia M and Shankar, Aditi G and Dent, Karin M and Anderson, Nick and Miller, Damon A and Futral, Brett T and Bamshad, Michael J} } @article {325, title = {The Centers for Mendelian Genomics: a new large-scale initiative to identify the genes underlying rare Mendelian conditions.}, journal = {Am J Med Genet A}, volume = {158A}, year = {2012}, month = {2012 Jul}, pages = {1523-5}, abstract = {

Next generation exome sequencing (ES) and whole genome sequencing (WGS) are new powerful tools for discovering the gene(s) that underlie Mendelian disorders. To accelerate these discoveries, the National Institutes of Health has established three Centers for Mendelian Genomics (CMGs): the Center for Mendelian Genomics at the University of Washington; the Center for Mendelian Genomics at Yale University; and the Baylor-Johns Hopkins Center for Mendelian Genomics at Baylor College of Medicine and Johns Hopkins University. The CMGs will provide ES/WGS and extensive analysis expertise at no cost to collaborating investigators where the causal gene(s) for a Mendelian phenotype has yet to be uncovered. Over the next few years and in collaboration with the global human genetics community, the CMGs hope to facilitate the identification of the genes underlying a very large fraction of all Mendelian disorders; see http://mendelian.org.

}, keywords = {Academies and Institutes, Genetic Diseases, Inborn, Genetics, Medical, Genome, Human, Genome-Wide Association Study, Genomics, High-Throughput Nucleotide Sequencing, Humans}, issn = {1552-4833}, doi = {10.1002/ajmg.a.35470}, author = {Bamshad, Michael J and Shendure, Jay A and Valle, David and Hamosh, Ada and Lupski, James R and Gibbs, Richard A and Boerwinkle, Eric and Lifton, Richard P and Gerstein, Mark and G{\"u}nel, Murat and Mane, Shrikant and Nickerson, Deborah A} }