Jason arrived 12 weeks early, on a rainy South Florida night in 1970, weighing four pounds and ten ounces. His delivery was precipitous, and he was intubated within minutes and transferred to the neonatal intensive care unit. There he was found to have severe anemia, bilateral inguinal hernias, and hypospadias. At 3 months of age, a bone marrow biopsy revealed erythroid and myeloid hypoplasia. Soon thereafter, he was taken to Harvard University and examined by Dr. Diamond, who, after reviewing the marrow results, confirmed the diagnosis that would bear his name: Diamond-Blackfan anemia (DBA) Diamond and Blackfan 1938. What followed was a childhood interrupted by red blood cell transfusions every 2 weeks, prednisone, and nightly chelation therapy with deferoxamine to slow the accumulation of iron throughout his body. But then, at age 17, Jason's hemoglobin levels suddenly stopped dropping. The transfusions were held for week after week, until it was concluded that he was in spontaneous remission. His body had finally, inexplicably, learned to do what it could not do before. Despite the elation and relief, the scars of his illness remained. He had already experienced developmental and growth delays, precocious puberty, hepatitis C infection, and herpes simplex keratitis, causing right eye blindness. In time, he would go on to develop nephrolithiasis, liver fibrosis, coronary artery disease, and bilateral hearing loss. Nevertheless, he persevered. With the support of physical, occupational and speech therapy throughout childhood, Jason ultimately earned a bachelor's degree in political science and built a career working in the scheduling department of an academic medical center. He led free trolley tours in the Everglades National Park, where he also discovered a passion for photography. He would go on to volunteer as a photographer for veterans' memorials across all four military branches, a commitment he sustained for 20 years. And of course, he provided tireless encouragement throughout the DBA community. “We have to have an attitude of ability, not disability,” he would often say. One day in 2016, while attending a conference, several adult friends with DBA mentioned that they now had a molecular diagnosis. The genetic etiology of Diamond-Blackfan anemia had been initially reported in 1999 in association with RPS19 and further delineated in the 2000s, predominantly involving pathogenic variants in ribosomal protein genes (Draptchinskaia et al. 1999). Jason had never undergone this testing and became determined to find out what had caused his disease and what had led to his remission. He obtained a referral to medical genetics and had a Diamond-Blackfan anemia panel performed that was negative. And then a bone marrow failure panel that was negative. Followed next by exome sequencing, which was again negative. Each result felt like a door closing. He had spent his adult life speaking about DBA and sharing his story with newly diagnosed families. And yet, without molecular confirmation, doubt ran through it all. What if his diagnosis had been wrong? What if he did not truly belong to the community around which he had built so much of his identity? By the time he enrolled in the Undiagnosed Diseases Network, he was desperate for an answer. Reviewing his records, we observed that the specimens previously used for testing had been drawn from blood. We had also hypothesized that his remission was due to acquired uniparental disomy in a hematopoietic progenitor cell, a mechanism known as revertant mosaicism (Garelli et al. 2019; Venugopal et al. 2017). If so, the loss of his disease-causing variant in blood cells, which had cured his anemia, would also be responsible for concealing the molecular cause of his disease. We sent a buccal specimen for genome sequencing, with plans for follow-up testing through a skin biopsy if necessary. The result, however, was unequivocal. Jason was heterozygous for an 811.76 kb deletion at 3q29 encompassing RPL35A and 12 additional genes. The RPL35A gene encodes ribosomal protein L35a of the 60S large subunit and was first associated with DBA in 2008 (Farrar et al. 2008). The phenotype associated with large deletions spanning RPL35A is known to be severe, and often includes steroid-resistant anemia, neutropenia, craniofacial anomalies, gastrointestinal complications, and intellectual disability (Gianferante et al. 2021). The variant had been there all along, waiting to be discovered. Jason was ebullient; his odyssey had ended. His journey illustrates the importance of specimen selection in patients with bone marrow failure, particularly in cases of suspected revertant mosaicism. Cultured skin fibroblasts remain the gold standard for germline testing, though buccal specimens may serve as a more accessible alternative, as they are less susceptible to leukocyte contamination than saliva (Theda et al. 2018). Furthermore, Jason's story demonstrates the value of persistence in the search for molecular diagnosis, despite years of inconclusive results. The absence of a molecular finding need not be accepted as a final answer, but rather, an invitation to return as technology and biological insights evolve. For Jason, the confirmation of his DBA diagnosis carries a meaning that is impossible to measure. The disease that had haunted him since before he could remember, the disease that took his childhood and continues to challenge him, was finally known, finally clear. It affirmed not only his clinical diagnosis but his lived experience and his place in a community that had given his suffering meaning. Fifty-three years after Dr. Diamond looked at a pale infant in Boston and knew what he was seeing, our patient, at last, felt he knew it too. We would like to thank the patient for his willingness to share his story and his decades of advocacy on behalf of the Diamond-Blackfan anemia community. We also thank the members of the Undiagnosed Diseases Network. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number 1U01HG010230. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Consortia members of the undiagnosed diseases network: Maria T. Acosta, David R. Adams, Ben Afzali, Ali Al-Beshri, Aimee Allworth, Raquel L. Alvarez, Justin Alvey, Ashley Andrews, Euan A. Ashley, Carlos A. 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Douine, Dawn Earl, Lisa T. Emrick, Christine M. Eng, Kimberly Ezell, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Jiayu Fu, William A. Gahl, Rebecca Ganetzky, Emily Glanton, Ian Glass, Page C. Goddard, Joanna M. Gonzalez, Andrea Gropman, Meghan C. Halley, Rizwan Hamid, Neal Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yan Huang, Anna Hurst, Wendy Introne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Emerald Kaitryn, Oguz Kanca, Yigit Karasozen, Shamika Ketkar, Dana Kiley, Gonench Kilich, Eric Klee, Shilpa N. Kobren, Isaac S. Kohane, Jennefer N. Kohler, Bruce Korf, Susan Korrick, Deborah Krakow, Elijah Kravets, Seema R. Lalani, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Kumarie Latchman, Kimberly LeBlanc, Brendan H. Lee, Richard A. Lewis, Pengfei Liu, Nicola Longo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, AudreyStephannie Maghiro, Rachel Mahoney, May Christine V. Malicdan, Rong Mao, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Allyn McConkie-Rosell, Alexa T. McCray, Matthew Might, Mohamad Mikati, Danny Miller, Ghayda Mirzaa, Breanna Mitchell, Paolo Moretti, Marie Morimoto, John J. Mulvihill, Lindsay Mulvihill, Mariko Nakano-Okuno, Stanley F. Nelson, Serena Neumann, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Neil H. Parker, LéShon Peart, Leoyklang Petcharet, John A. Phillips III, Filippo Pinto e Vairo, Jennifer E. Posey, Lorraine Potocki, Barbara N. Pusey Swerdzewski, Aaron Quinlan, Daniel J. Rader, Ramakrishnan Rajagopalan, Deepak A. Rao, Anna Raper, Wendy Raskind, Adriana Rebelo, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Martin Rodriguez, Jill A. Rosenfeld, Elizabeth Rosenthal, Francis Rossignol, Maura Ruzhnikov, Marla Sabaii, Jacinda B. Sampson, Timothy Schedl, Lisa Schimmenti, Kelly Schoch, Daryl A. Scott, Elaine Seto, Vandana Shashi, Emily Shelkowitz, Sam Sheppeard, Jimann Shin, Edwin K. Silverman, Giorgio Sirugo, Kathy Sisco, Tammi Skelton, Cara Skraban, Carson A. Smith, Kevin S. Smith, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Andrew Stergachis, Joan M. Stoler, Kathleen Sullivan, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Queenie Tan, Amelia L. M. Tan, Arjun Tarakad, Herman Taylor, Mustafa Tekin, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Rachel A. Ungar, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Nicole M. Walley, Jennifer Wambach, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Monika Weisz Hubshman, Mark Wener, Tara Wenger, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Heidi Wood, Kim Worley, Shinya Yamamoto, Zhe Zhang, Stephan Zuchner. This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, UO1 NS134353. Written informed consent was obtained from the patient for publication of this report. The patient reviewed and approved the final manuscript. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Borja et al. (Fri,) studied this question.