Browsing by Author "Hufnagel, Robert B."

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    Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia
    (Elsevier, 2015-04-02) Gordon, Christopher T.; Weaver, K. Nicole; Zechi-Ceide, Roseli Maria; Madsen, Erik C.; Tavares, Andre L.P.; Oufadem, Myriam; Kurihara, Yukiko; Adameyko, Igor; Picard, Arnaud; Breton, Sylvain; Pierrot, Se´bastien; Biosse-Duplan, Martin; Voisin, Norine; Masson, Cecile; Bole-Feysot, Christine; Nitschke´, Marie-Ange; Lacombe, Didier; Guion-Almeida, Maria Leine; Moura, Priscila Padilha; Garib, Daniela Gamba; Munnich, Arnold; Ernfors, Patrik; Hufnagel, Robert B.; Hopkin, Robert J.; Kurihara, Hiroki; Saal, Howard M.; Weaver, David D.; Katsanis, Nicholas; Lyonnet, Stanislas; Golzio, Christelle; Clouthier, David E.; Amiel, Jeanne; Department of Medical & Molecular Genetics, IU School of Medicine
    The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.
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    The challenges and opportunities of offering and integrating training in clinical molecular genetics and clinical cytogenetics: A survey of LGG Fellowship Program Directors
    (Elsevier, 2024) Deignan, Joshua L.; Aggarwal, Vimla; Bale, Allen E.; Bellissimo, Daniel B.; Booker, Jessica K.; Cao, Yang; Crooks, Kristy R.; Deak, Kristen L.; Del Gaudio, Daniela; Funke, Birgit; Hoppman, Nicole L.; Horner, Vanessa; Hufnagel, Robert B.; Jackson-Cook, Colleen; Koduru, Prasad; Leung, Marco L.; Li, Shibo; Liu, Pengfei; Mao, Minjie Luo Rong; Mason-Suares, Heather; Mikhail, Fady M.; Moore, Stephen R.; Naeem, Rizwan C.; Pollard, Laura M.; Repnikova, Elena A.; Shao, Lina; Shaw, Brandon M.; Shetty, Shashirekha; Smolarek, Teresa A.; Spiteri, Elizabeth; Van Ziffle, Jessica; Vance, Gail H.; Vnencak-Jones, Cindy L.; Williams, Eli S.; Medical and Molecular Genetics, School of Medicine
    Purpose: The specialty of Laboratory Genetics and Genomics (LGG) was created in 2017 in an effort to reflect the increasing convergence in technologies and approaches between clinical molecular genetics and clinical cytogenetics. However, there has not yet been any formal evaluation of the merging of these disciplines and the challenges faced by Program Directors (PDs) tasked with ensuring the successful training of laboratory geneticists under the new model. Methods: An electronic multi-question Qualtrics survey was created and was sent to the PD for each of the Accreditation Council for Graduate Medical Education-accredited LGG fellowship programs at the time. The data were collected, and the responses were aggregated for each question. Results: All of the responding PDs had started training at least 1 LGG fellow. PDs noted challenges with funding, staff shortages, molecular/cytogenetics content integration, limited total training time, increased remote work, increased sendout testing, and a lack of prior cytogenetics knowledge among incoming fellows. Conclusion: This survey attempted to assess the challenges that LGG PDs have been facing in offering and integrating clinical molecular genetics and clinical cytogenetics fellowship training. Common challenges between programs were noted, and a set of 6 concluding comments are provided to facilitate future discussion.