%0 Journal Article %J Genet Med %D 2022 %T Centers for Mendelian Genomics: A decade of facilitating gene discovery. %A Baxter, Samantha M %A Posey, Jennifer E %A Lake, Nicole J %A Sobreira, Nara %A Chong, Jessica X %A Buyske, Steven %A Blue, Elizabeth E %A Chadwick, Lisa H %A Coban-Akdemir, Zeynep H %A Doheny, Kimberly F %A Davis, Colleen P %A Lek, Monkol %A Wellington, Christopher %A Jhangiani, Shalini N %A Gerstein, Mark %A Richard A Gibbs %A Lifton, Richard P %A MacArthur, Daniel G %A Matise, Tara C %A James R Lupski %A Valle, David %A Bamshad, Michael J %A Hamosh, Ada %A Mane, Shrikant %A Nickerson, Deborah A %A Rehm, Heidi L %A O'Donnell-Luria, Anne %K Exome %K Exome Sequencing %K Genetic Association Studies %K Genomics %K Humans %K Phenotype %X

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration.

METHODS: Over the past 10 years, the National Institutes of Health-supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution.

RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher.

CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

%B Genet Med %V 24 %P 784-797 %8 2022 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/35148959?dopt=Abstract %R 10.1016/j.gim.2021.12.005 %0 Journal Article %J Genet Med %D 2019 %T Insights into genetics, human biology and disease gleaned from family based genomic studies. %A Posey, Jennifer E %A O'Donnell-Luria, Anne H %A Chong, Jessica X %A Harel, Tamar %A Jhangiani, Shalini N %A Coban Akdemir, Zeynep H %A Buyske, Steven %A Pehlivan, Davut %A Carvalho, Claudia M B %A Baxter, Samantha %A Sobreira, Nara %A Liu, Pengfei %A Wu, Nan %A Rosenfeld, Jill A %A Kumar, Sushant %A Avramopoulos, Dimitri %A White, Janson J %A Doheny, Kimberly F %A Witmer, P Dane %A Boehm, Corinne %A Sutton, V Reid %A Donna M Muzny %A Eric Boerwinkle %A Gunel, Murat %A Nickerson, Deborah A %A Mane, Shrikant %A MacArthur, Daniel G %A Richard A Gibbs %A Hamosh, Ada %A Lifton, Richard P %A Matise, Tara C %A Rehm, Heidi L %A Gerstein, Mark %A Bamshad, Michael J %A Valle, David %A Lupski, James R %K Databases, Genetic %K Exome Sequencing %K Genetic Diseases, Inborn %K Genetic Heterogeneity %K Genetic Predisposition to Disease %K Genome, Human %K Genomics %K Humans %K National Institutes of Health (U.S.) %K Pedigree %K United States %X

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.

%B Genet Med %V 21 %P 798-812 %8 2019 Apr %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/30655598?dopt=Abstract %R 10.1038/s41436-018-0408-7 %0 Journal Article %J Am J Hum Genet %D 2015 %T The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. %A Chong, Jessica X %A Buckingham, Kati J %A Jhangiani, Shalini N %A Boehm, Corinne %A Sobreira, Nara %A Smith, Joshua D %A Harrell, Tanya M %A McMillin, Margaret J %A Wiszniewski, Wojciech %A Gambin, Tomasz %A Coban Akdemir, Zeynep H %A Doheny, Kimberly %A Scott, Alan F %A Avramopoulos, Dimitri %A Chakravarti, Aravinda %A Hoover-Fong, Julie %A Mathews, Debra %A Witmer, P Dane %A Ling, Hua %A Hetrick, Kurt %A Watkins, Lee %A Patterson, Karynne E %A Reinier, Frederic %A Blue, Elizabeth %A Muzny, Donna %A Kircher, Martin %A Bilguvar, Kaya %A López-Giráldez, Francesc %A Sutton, V Reid %A Tabor, Holly K %A Leal, Suzanne M %A Gunel, Murat %A Mane, Shrikant %A Gibbs, Richard A %A Boerwinkle, Eric %A Hamosh, Ada %A Shendure, Jay %A Lupski, James R %A Lifton, Richard P %A Valle, David %A Nickerson, Deborah A %A Bamshad, Michael J %K Genetic Diseases, Inborn %K Genetics, Medical %K Humans %K Phenotype %K Proteins %X

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

%B Am J Hum Genet %V 97 %P 199-215 %8 2015 Aug 06 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/26166479?dopt=Abstract %R 10.1016/j.ajhg.2015.06.009 %0 Journal Article %J Am J Med Genet A %D 2012 %T The Centers for Mendelian Genomics: a new large-scale initiative to identify the genes underlying rare Mendelian conditions. %A Bamshad, Michael J %A Shendure, Jay A %A Valle, David %A Hamosh, Ada %A Lupski, James R %A Gibbs, Richard A %A Boerwinkle, Eric %A Lifton, Richard P %A Gerstein, Mark %A Gunel, Murat %A Mane, Shrikant %A Nickerson, Deborah A %K Academies and Institutes %K Genetic Diseases, Inborn %K Genetics, Medical %K Genome, Human %K Genome-Wide Association Study %K Genomics %K High-Throughput Nucleotide Sequencing %K Humans %X

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.

%B Am J Med Genet A %V 158A %P 1523-5 %8 2012 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/22628075?dopt=Abstract %R 10.1002/ajmg.a.35470