Molecular pathology selected abstracts

Create PDF

Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; Andrés G. Madrigal, MD, PhD, assistant professor, clinical, Ohio State University Wexner Medical Center, Columbus; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; and Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center.

Study of a newborn with atypical hemolytic uremic syndrome

Augstus 2023—Atypical hemolytic uremic syndrome is a rare, potentially life-threatening thrombotic microangiopathy. The disorder causes tiny blood clots to form in blood vessels and results in organ damage. Clinical findings in atypical hemolytic uremic syndrome (aHUS) include hemolytic anemia, low platelet count, and acute kidney failure. In many cases, HUS is caused by Shiga toxin-producing E. coli, other infections, or certain medications, or it can result from other health conditions. The label “atypical” is used to delineate hemolytic uremic syndrome that is not due to any of these common causes. Research shows that dysregulation of the complement system is a major contributor to the clinical manifestations of aHUS. The complement system is an important component of the innate immune defense system, which is the body’s first line of defense against pathogens. It is made up of multiple plasma proteins that opsonize foreign targets and induce inflammatory responses to fight infection, and it can assemble into a membrane-attack complex to puncture the membrane of targeted cells. The complement system is also a highly regulated noncellular system for preventing lysis of host cells. Dysregulation of the complement system can result in inadvertent attacks on host endothelial cells, resulting in endothelial cell damage, formation of microthrombi, consumption of platelets, mechanical disruption of red blood cells, and organ damage characteristic of aHUS. Loss-of-function alterations in genes that encode components regulating the complement system and gain-of-function alterations in genes that encode complement activators have been identified in patients with aHUS. Because aHUS is usually triggered by an environmental agent or health condition, these genetic aberrations are considered risk factors for developing the disease. While genetic abnormalities are seen in some cases of aHUS, 30 to 50 percent of cases have no known underlying genetic alteration. The authors of this study described a clinical case involving a newborn boy with aHUS who was responsive to anticomplement antibody treatment. Whole exome sequencing identified a de novo germline missense mutation in C1GALT1C1:c.266 C>T,p.(T89I) on chromosome X. Other laboratory studies of the patient were negative for HUS-associated infections, defects in other aHUS-associated genes, and significant copy number variations. C1GALT1C1 encodes the protein C1GALT1C1, known as Cosmc. This protein is a key component of the glycosylation pathway and adds galactose to the GalNac monosaccharide on serine or threonine residues to form the T antigen. Normally, other enzymes then add other sugar moieties to this highly immunogenic T antigen. However, in certain disease states, the T antigen becomes exposed, is detected by the immune system, and triggers the complement cascade resulting in HUS. Laboratory testing showed that the patient’s C1GALT1C1 mutation resulted in a persistently exposed T antigen, even during treatment with anticomplement antibody therapy. The study findings not only identify a novel mutation in a potentially devastating, yet treatable, rare disease, but they re-emphasize the dangers surrounding the production of neoantigens in disease and raise further questions about complement activation for patient-tailored therapeutic intervention.

Hadar N, Schreiber R, Eskin-Schwartz M, et al. X-linked C1GALT1C1 mutation causes atypical hemolytic uremic syndrome. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-022-01278-5

Correspondence: Dr. Ohad S. Birk at obirk@bgu.ac.il