Citations 2
A Review of Multiple Diagnostic Approaches in the Undiagnosed Diseases Network to Identify Inherited Metabolic Diseases
Furuta, Yutaka , Tinker, Rory J. , Hamid, Rizwan , Ezell, Kimberly , Oglesbee, Devin , DeBerardinis, Ralph J., Phillips, John A., Oglesbee, Devin , Tinker, R J , Cogan, Joy D. , DeBerardinis, Ralph J. , Phillips, John A., Network, the Undiagnosed Diseases
No container title available | October 11, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Background The number of known inherited metabolic diseases (IMDs) has been expanding, and the rate of diagnosis is improving with the development of innovative approaches including next generation sequencing (NGS). However, a substantial proportion of IMDs remain undetected by traditional diagnostic approaches. We aim to highlight the spectrum of IMDs diagnosed by the Undiagnosed Diseases Network (UDN) and to learn from the UDN diagnostic processes that were able to detect IMDs. Methods We conducted a retrospective analysis of 757 UDN participants diagnosed from 2015 until 2023 using the cohort database, which were divided into a cohort with IMDs (n = 194; 27%) and a cohort whose phenotypes were not explained by an IMD (n = 563; 73%), based on the International Classification of Inherited Metabolic Disorders (ICIMD). Then, we divided the causes of the metabolic 194 diagnoses into seven groups that included all the ICIMD categories. We inspected which clinical and laboratory approaches contributed to a final UDN diagnosis. We also present a UDN case example from each group to highlight the diagnostic yields that resulted from combining newer diagnostic approaches in the UDN and illustrate potential pitfalls of current NGS methods. Results These 194 cases of IMDs included examples from 21/25 (84%) of the ICIMD categories. Of the UDN subjects 164/194 (85%) were diagnosed with IMDs through NGS. Conclusion The spectrum of IMDs detected in the UDN cohort is large and growing and appropriate use of newer multiple diagnostic approaches should further increase diagnosis of IMDs that are presently missed by the traditional laboratory screening methods.
TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system
Akula, Shyam K. , Marciano, Jack H. , Lim, Youngshin , Exposito-Alonso, David , Hylton, Norma K. , Hwang, Grace H. , Neil, Jennifer E., Dominado, Nicole , Bunton-Stasyshyn, Rosie , Song, Janet , Talukdar, Maya , Schmid, Aloisia, Teboul, Lydia , Mo, Alisa , Finander, Benjamin , Beck, Samantha G., Yeh, Rebecca C., Otani, Aoi, Qian, Xuyu , DeGennaro, Ellen M. , Alkuraya, Fowzan S. , Maddirevula, Sateesh , Cascino, Gregory D. , Network, Undiagnosed Diseases, Burrage, Lindsay C. , Rosenfield, Jill A., Ketkar, Shamika , Clark, Gary, Bacino, Carlos A. , Lewis, Richard A. , Segal, Rosalind A. , Bazán, J. Fernando , Smith, K. A. , Golden, Jeffrey A. , Cho, Ginam , Walsh, Christopher A. , Alejandro, Mercedes E., Ashley, Euan A. , Baker, Eva H. , Balasubramanyam, Ashok , Barseghyan, Hayk , Batzli, Gabriel F., Bernstein, Jonathan A. , Bican, Anna, Bick, David , Birch, Camille L., Boone, Braden, Bostwick, Bret L. , Briere, Lauren C. , Brokamp, Elly , Brush, Matthew , Chen, Shan , Coakley, Terra R., Cobban, Laurel A., Colley, Heather A., Cooper, Cynthia M. , Craigen, William J., D’Souza, Precilla , Davids, Mariska, Davidson, Jean M. , Dayal, Jyoti G. , Dell’Angelica, Esteban C., Dhar, Shweta U. , Dipple, Katrina M. , Dorrani, Naghmeh, Dorset, Daniel C., Douglas, Jessica, Draper, David D., Dries, Annika M., Eckstein, David J. , Emrick, Lisa , Eng, Christine M. , Enns, Gregory M. , Eskin, Ascia , Esteves, Cecilia, Estwick, Tyra, Fernández, Liliana, Fogel, Brent L. , Friedman, Noah D., Gahl, William A. , Godfrey, Rena A., Goldstein, David B. , Gould, Sarah E., Groden, Catherine, Hamid, Rizwan , Hanchard, Neil A. , High, Frances A. , Hom, Jason , Howerton, Ellen M. , Jamal, Fariha , Jiang, Yong‐hui , Johnston, Jean M., Karaviti, Lefkothea , Kelley, Emily G., Koeller, David M. , Kohane, Isaac S. , Kohler, Jennefer N., Korrick, Susan , Kozuira, Mary, Krasnewich, Donna M., Krier, Joel B. , Lau, C. Christopher, Lazar, Jozef, LeBlanc, Kimberly , Lee, Brendan , Lee, Hane , Lewis, Richard A., Loscalzo, Joseph, Maas, Richard L., MacRae, Calum A. , Maduro, Valerie V. , Majcherska, Marta M., Malicdan, May Christine V. , Mamounas, Laura A., Manolio, Teri A. , Markello, Thomas C. , Martín, Martín G., Marwaha, Shruti , May, Thomas , McConkie‐Rosell, Allyn , McCormack, Colleen E., McCray, Alexa T. , Merker, Jason D. , Moretti, Paolo , Morimoto, Marie , Murdock, David R. , Muzny, Donna M., Nehrebecky, Michele, Nelson, Stan F., Newberry, J. Scott, Newman, John H. , Nicholas, Sarah K. , Novacic, Donna, Orengo, James P. , Pallais, J. Carl , Palmer, Christina G.S. , Papp, Jeanette C. , Parker, Neil H., Peña, Loren D.M. , Phillips, John A., Potocki, Lorraine , Pusey, Barbara N., Renteria, Genecee, Rives, Lynette, Robertson, Amy K., Rodan, Lance H. , Sampson, Jacinda B. , Samson, Susan L. , Schoch, Kelly, Shakachite, Lisa, Sharma, Prashant , Shashi, Vandana , Signer, Rebecca , Silverman, Edwin K. , Smith, Kevin S., Spillmann, Rebecca C. , Stoler, Joan M. , Sullivan, Jennifer A. , Tan, Queenie K.‐G., Tan, Wen-Haan, Toro, Camilo , Tran, Alyssa A., Urv, Tiina K. , Vogel, Tiphanie P. , Waggott, Daryl, Wahl, Colleen E., Walker, Melissa , Walley, Nicole M., Wan, Jijun , Ward, Patricia A., Westerfield, Monte, Wise, Anastasia L., Wolfe, Lynne A. , Yang, Yaping , Yoon, Amanda J., Yu, Guoyun, Zastrow, Diane B. , Zhao, Chunli , Zheng, Allison, Bunton-Stasyshyn, Rosie K , DeGennaro, Ellen M , Cascino, Gregory D , Giannini, Caterina , Burrage, Lindsay C , Rosenfield, Jill A , Bacino, Carlos , Lewis, Richard A , Segal, Rosalind A , Bazan, J Fernando , Smith, Kelly A , Golden, Jeffrey A , Cho, Ginam , Walsh, Christopher A , Alkuraya, Fowzan S , Akula, Shyam K , Shin, Taehwan , Giannini, Caterina , Network, Undiagnosed Diseases, Adams, David R. , Aday, Aaron W. , Allard, Patrick , Azamian, Mahshid S. , Beggs, Alan H. , Behnam, Babak , Bellen, Hugo J. , Berry, Gerard T. , Bonner, Devon E. , Brown, Donna M. , Burke, Elizabeth A. , Butte, Manish J. , Cogan, Joy D. , Cope, Heidi , D’Souza, Precilla , Douine, Emilie D. , Ferreira, Carlos R , Fieg, Elizabeth L. , Fisher, Paul Graham , Goldman, Alica M. , Gourdine, Jean-Philippe F. , Gropman, Andrea L , Haendel, Melissa , Holm, Ingrid A. , Huang, Yong , Jones, Angela , Kyle, Jennifer E , Lalani, Seema R , Levy, Shawn , Lewis, Richard A., Loo, Sandra K. , Macnamara, Ellen F. , Marom, Ronit , Martínez-Agosto, Julián A. , May, Thomas, Metz, Thomas , Might, Matthew , Mochida, Ganeshwaran H. , Mulvihill, John Joseph , Murphy, Jennifer L. , Muzny, Donna M. , Orange, Jordan S. , Phillips, John A., Posey, Jennifer E , Postlethwait, John H. , Reuter, Chloe M. , Rosenfeld, Jill A. , Scott, Daryl A , Sinsheimer, Janet S. , Stong, Nicholas , Sweetser, David A , Tifft, Cynthia , Vilain, Eric J. N. , Walley, Nicole M., Wangler, Michael F , Waters, Katrina M. , Webb‐Robertson, Bobbie‐Jo , Wheeler, Matthew T , Worthey, Elizabeth A. , Yamamoto, Shinya , Yang, John Jeongseok
Proceedings of the National Academy of Sciences | January 20, 2023 | Volume: 120 | Issue: 4 | Pages: No page available
Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B , which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.