Browsing by Author "Orwig, Kyle"

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    Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability
    (Elsevier, 2022-02-15) Teekakirikul, Polakit; Zhu, Wenjuan; Xu, Xinxiu; Young, Cullen B.; Tan, Tuantuan; Smith, Amanda M.; Wang, Chengdong; Peterson, Kevin A.; Gabriel, George C.; Ho, Sebastian; Sheng, Yi; de Bellaing, Anne Moreau; Sonnenberg, Daniel A.; Lin, Jiuann-huey; Fotiou, Elisavet; Tenin, Gennadiy; Wang, Michael X.; Wu, Yijen L.; Feinstein, Timothy; Devine, William; Gou, Honglan; Bais, Abha S.; Glennon, Benjamin J.; Zahid, Maliha; Wong, Timothy C.; Ahmad, Ferhaan; Rynkiewicz, Michael J.; Lehman, William J.; Keavney, Bernard; Alastalo, Tero-Pekka; Freckmann, Mary-Louise; Orwig, Kyle; Murray, Steve; Ware, Stephanie M.; Zhao, Hui; Feingold, Brian; Lo, Cecilia W.; Pediatrics, School of Medicine
    Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.
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    The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond.
    (Future Medicine, 2018-12) Smith, Brigid M.; Duncan, Francesca E.; Ataman, Lauren; Smith, Kristin; Quinn, Gwendolyn P.; Chang, R. Jeffrey; Finlayson, Courtney; Orwig, Kyle; Valli-Pulaski, Hanna; Moravek, Molly B.; Zelinski, Mary B.; Irene Su, H.; Vitek, Wendy; Smith, James F.; Jeruss, Jacqueline S.; Gracia, Clarisa; Coutifaris, Christos; Shah, Divya; Nahata, Leena; Gomez-Lobo, Veronica; Appiah, Leslie Coker; Brannigan, Robert E.; Gillis, Valerie; Gradishar, William; Javed, Asma; Rhoton-Vlasak, Alice S.; Kondapalli, Laxmi A.; Neuber, Evelyn; Ginsberg, Jill P.; Muller, Charles H.; Hirshfeld-Cytron, Jennifer; Kutteh, William H.; Lindheim, Steven R.; Cherven, Brooke; Meacham, Lillian R.; Rao, Pooja; Torno, Lilibeth; Sender, Leonard S.; Vadaparampil, Susan T.; Skiles, Jodi L.; Schafer-Kalkhoff, Tara; Frias, Oliva J.; Byrne, Julia; Westphal, Lynn M.; Schust, Danny J.; Klosky, James L.; McCracken, Kate A.; Ting, Alison; Khan, Zaraq; Granberg, Candace; Lockart, Barbara; Scoccia, Bert; Laronda, Monica M.; Mersereau, Jennifer E.; Marsh, Courtney; Pavone, Mary Ellen; Woodruff, Teresa K.; Pediatrics, School of Medicine
    Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.