Camille A. Dash1, Jill A. Madden2,3, Christy Cummings1, Melissa Rose4, Sheria D. Wilson5,6, Mari Mori6, Pankaj B. Agrawal3,7, Bimal P. Chaudhari5,6,8 and Monica H. Wojcik1,2,3 1Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA; 2Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA; 3The Manton Center for Orphan Disease Research, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA; 4Division of Hematology, Oncology, and Bone Marrow Transplant, Department of Pediatrics, Nationwide Children's Hospital and the Ohio State University College of Medicine, Columbus, Ohio 43205, USA; 5Division of Neonatology, Department of Pediatrics, Nationwide Children's Hospital and the Ohio State University College of Medicine, Columbus, Ohio 43205, USA; 6Division of Genetics and Genomic Medicine, Department of Pediatrics, Nationwide Children's Hospital and the Ohio State University College of Medicine, Columbus, Ohio 43205, USA; 7Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children's Hospital, Jackson Health System, Miami, Florida 33136, USA; 8Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA Corresponding author: monica.wojcikchildrens.harvard.edu Abstract

Pathogenic variants in MECOM, a gene critical to the self-renewal and proliferation of hematopoietic stem cells, are known to cause a rare bone marrow failure syndrome associated with amegakaryocytic thrombocytopenia and bilateral radioulnar synostosis known as RUSAT2. However, the spectrum of disease seen with causal variants in MECOM is broad, ranging from mildly affected adults to fetal loss. We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages; radioulnar synostosis was not observed in either patient, and, unfortunately, neither infant survived. In both cases, genomic sequencing revealed de novo variants in MECOM considered to be responsible for their severe presentations. These cases add to the growing body of literature that describe MECOM-associated disease, particularly MECOM as a cause of fetal hydrops due to bone marrow failure in utero. Furthermore, they support the use of a broad sequencing approach for perinatal diagnosis, as MECOM is absent from available targeted gene panels for hydrops, and highlight the importance of postmortem genomic investigation.

Received April 10, 2023. Accepted May 16, 2023.