Browsing by Author "Davis, Erica E"

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    A Genocentric Approach to Discovery of Mendelian Disorders.
    (American journal of human genetics, 2019-11) Hansen, Adam W; Murugan, Mullai; Li, He; Khayat, Michael M; Wang, Liwen; Rosenfeld, Jill; Andrews, B Kim; Jhangiani, Shalini N; Coban Akdemir, Zeynep H; Sedlazeck, Fritz J; Ashley-Koch, Allison E; Liu, Pengfei; Muzny, Donna M; Task Force for Neonatal Genomics; Davis, Erica E; Katsanis, Nicholas; Sabo, Aniko; Posey, Jennifer E; Yang, Yaping; Wangler, Michael F; Eng, Christine M; Sutton, V Reid; Lupski, James R; Boerwinkle, Eric; Gibbs, Richard A
    The advent of inexpensive, clinical exome sequencing (ES) has led to the accumulation of genetic data from thousands of samples from individuals affected with a wide range of diseases, but for whom the underlying genetic and molecular etiology of their clinical phenotype remains unknown. In many cases, detailed phenotypes are unavailable or poorly recorded and there is little family history to guide study. To accelerate discovery, we integrated ES data from 18,696 individuals referred for suspected Mendelian disease, together with relatives, in an Apache Hadoop data lake (Hadoop Architecture Lake of Exomes [HARLEE]) and implemented a genocentric analysis that rapidly identified 154 genes harboring variants suspected to cause Mendelian disorders. The approach did not rely on case-specific phenotypic classifications but was driven by optimization of gene- and variant-level filter parameters utilizing historical Mendelian disease-gene association discovery data. Variants in 19 of the 154 candidate genes were subsequently reported as causative of a Mendelian trait and additional data support the association of all other candidate genes with disease endpoints.
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    De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.
    (American journal of human genetics, 2019-03) Helbig, Katherine L; Lauerer, Robert J; Bahr, Jacqueline C; Souza, Ivana A; Myers, Candace T; Uysal, Betül; Schwarz, Niklas; Gandini, Maria A; Huang, Sun; Keren, Boris; Mignot, Cyril; Afenjar, Alexandra; Billette de Villemeur, Thierry; Héron, Delphine; Nava, Caroline; Valence, Stéphanie; Buratti, Julien; Fagerberg, Christina R; Soerensen, Kristina P; Kibaek, Maria; Kamsteeg, Erik-Jan; Koolen, David A; Gunning, Boudewijn; Schelhaas, H Jurgen; Kruer, Michael C; Fox, Jordana; Bakhtiari, Somayeh; Jarrar, Randa; Padilla-Lopez, Sergio; Lindstrom, Kristin; Jin, Sheng Chih; Zeng, Xue; Bilguvar, Kaya; Papavasileiou, Antigone; Xing, Qinghe; Zhu, Changlian; Boysen, Katja; Vairo, Filippo; Lanpher, Brendan C; Klee, Eric W; Tillema, Jan-Mendelt; Payne, Eric T; Cousin, Margot A; Kruisselbrink, Teresa M; Wick, Myra J; Baker, Joshua; Haan, Eric; Smith, Nicholas; Sadeghpour, Azita; Davis, Erica E; Katsanis, Nicholas; Task Force for Neonatal Genomics; Corbett, Mark A; MacLennan, Alastair H; Gecz, Jozef; Biskup, Saskia; Goldmann, Eva; Rodan, Lance H; Kichula, Elizabeth; Segal, Eric; Jackson, Kelly E; Asamoah, Alexander; Dimmock, David; McCarrier, Julie; Botto, Lorenzo D; Filloux, Francis; Tvrdik, Tatiana; Cascino, Gregory D; Klingerman, Sherry; Neumann, Catherine; Wang, Raymond; Jacobsen, Jessie C; Nolan, Melinda A; Snell, Russell G; Lehnert, Klaus; Sadleir, Lynette G; Anderlid, Britt-Marie; Kvarnung, Malin; Guerrini, Renzo; Friez, Michael J; Lyons, Michael J; Leonhard, Jennifer; Kringlen, Gabriel; Casas, Kari; El Achkar, Christelle M; Smith, Lacey A; Rotenberg, Alexander; Poduri, Annapurna; Sanchis-Juan, Alba; Carss, Keren J; Rankin, Julia; Zeman, Adam; Raymond, F Lucy; Blyth, Moira; Kerr, Bronwyn; Ruiz, Karla; Urquhart, Jill; Hughes, Imelda; Banka, Siddharth; Deciphering Developmental Disorders Study; Hedrich, Ulrike BS; Scheffer, Ingrid E; Helbig, Ingo; Zamponi, Gerald W; Lerche, Holger; Mefford, Heather C
    (The American Journal of Human Genetics 103, 666–678; November 1, 2018) In the version of this article originally published online, Qinghe Xing's name was misspelled as Qinghe Xin. Also, Azita Sadeghpour, Erica E. Davis, and Nicholas Katsanis (all at Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA) and the Task Force for Neonatal Genomics were omitted from the author list. The members of the Task Force for Neonatal Genomics are as follows: Alexander Allori, Misha Angrist, Patricia Ashley, Margarita Bidegain, Brita Boyd, Eileen Chambers, Heidi Cope, C. Michael Cotten, Theresa Curington, Erica E. Davis, Sarah Ellestad, Kimberley Fisher, Amanda French, William Gallentine, Ronald Goldberg, Kevin Hill, Sujay Kansagra, Nicholas Katsanis, Sara Katsanis, Joanne Kurtzberg, Jeffrey Marcus, Marie McDonald, Mohammed Mikati, Stephen Miller, Amy Murtha, Yezmin Perilla, Carolyn Pizoli, Todd Purves, Sherry Ross, Azita Sadeghpour, Edward Smith, and John Wiener. The authors apologize for these omissions.
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    Identification of cis-suppression of human disease mutations by comparative genomics.
    (Nature, 2015-08) Jordan, Daniel M; Frangakis, Stephan G; Golzio, Christelle; Cassa, Christopher A; Kurtzberg, Joanne; Task Force for Neonatal Genomics; Davis, Erica E; Sunyaev, Shamil R; Katsanis, Nicholas
    Patterns of amino acid conservation have served as a tool for understanding protein evolution. The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients. Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity.
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    In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
    (PLoS Genet, 2015-07) Anderson, Blair R; Howell, David N; Soldano, Karen; Garrett, Melanie E; Katsanis, Nicholas; Telen, Marilyn J; Davis, Erica E; Ashley-Koch, Allison E
    African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms.
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    Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies.
    (American journal of human genetics, 2019-01) Khan, Tahir N; Khan, Kamal; Sadeghpour, Azita; Reynolds, Hannah; Perilla, Yezmin; McDonald, Marie T; Gallentine, William B; Baig, Shahid M; Task Force for Neonatal Genomics; Davis, Erica E; Katsanis, Nicholas
    The use of whole-exome and whole-genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here, we report on two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous NPHP1 deletion, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules in zebrafish larvae. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy, and they highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus.
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    Participant-Partners in Genetic Research: An Exome Study with Families of Children with Unexplained Medical Conditions
    (Journal of Participatory Medicine, 2018) Katsanis, Sara Huston; Minear, Mollie A; Sadeghpour, Azita; Cope, Heidi; Perilla, Yezmin; Cook-Deegan, Robert; Duke Task Force For Neonatal Genomics; Katsanis, Nicholas; Davis, Erica E; Angrist, Misha
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    Rapid and Efficient Generation of Transgene-Free iPSC from a Small Volume of Cryopreserved Blood.
    (Stem cell reviews and reports, 2015-08) Zhou, Hongyan; Martinez, Hector; Sun, Bruce; Li, Aiqun; Zimmer, Matthew; Katsanis, Nicholas; Davis, Erica E; Kurtzberg, Joanne; Lipnick, Scott; Noggle, Scott; Rao, Mahendra; Chang, Stephen
    Human peripheral blood and umbilical cord blood represent attractive sources of cells for reprogramming to induced pluripotent stem cells (iPSCs). However, to date, most of the blood-derived iPSCs were generated using either integrating methods or starting from T-lymphocytes that have genomic rearrangements thus bearing uncertain consequences when using iPSC-derived lineages for disease modeling and cell therapies. Recently, both peripheral blood and cord blood cells have been reprogrammed into transgene-free iPSC using the Sendai viral vector. Here we demonstrate that peripheral blood can be utilized for medium-throughput iPSC production without the need to maintain cell culture prior to reprogramming induction. Cell reprogramming can also be accomplished with as little as 3000 previously cryopreserved cord blood cells under feeder-free and chemically defined Xeno-free conditions that are compliant with standard Good Manufacturing Practice (GMP) regulations. The first iPSC colonies appear 2-3 weeks faster in comparison to previous reports. Notably, these peripheral blood- and cord blood-derived iPSCs are free of detectable immunoglobulin heavy chain (IGH) and T cell receptor (TCR) gene rearrangements, suggesting they did not originate from B- or T- lymphoid cells. The iPSCs are pluripotent as evaluated by the scorecard assay and in vitro multi lineage functional cell differentiation. Our data show that small volumes of cryopreserved peripheral blood or cord blood cells can be reprogrammed efficiently at a convenient, cost effective and scalable way. In summary, our method expands the reprogramming potential of limited or archived samples either stored at blood banks or obtained from pediatric populations that cannot easily provide large quantities of peripheral blood or a skin biopsy.
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    Temperature-activated ion channels in neural crest cells confer maternal fever-associated birth defects.
    (Science signaling, 2017-10) Hutson, Mary R; Keyte, Anna L; Hernández-Morales, Miriam; Gibbs, Eric; Kupchinsky, Zachary A; Argyridis, Ioannis; Erwin, Kyle N; Pegram, Kelly; Kneifel, Margaret; Rosenberg, Paul B; Matak, Pavle; Xie, Luke; Grandl, Jörg; Davis, Erica E; Katsanis, Nicholas; Liu, Chunlei; Benner, Eric J
    Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency-controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.