1. Pretransplant Genetic Susceptibility: Clinical Relevance in Transplant-Associated Thrombotic Microangiopathy
- Author
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Robert A. Brodsky, Jacob Passweg, Panagiotis Tsirigotis, Emmanuel Nikolousis, Ioannis Batsis, Maria Tsagiopoulou, Ioannis Baltadakis, Kostas Stamatopoulos, Pat Taylor, Tasoula Touloumenidou, Achilles Anagnostopoulos, Dimitrios A. Tsakiris, Apostolia Papalexandri, Eleni Gavriilaki, Andreas Holbro, Nikolaos Charchalakis, Despina Mallouri, Ioanna Sakellari, Maria Liga, Maria Stamouli, Alexandros Spyridonidis, Fotis Psomopoulos, Evangelia Yannaki, and Maria Koutra
- Subjects
Adult ,Male ,0301 basic medicine ,Untranslated region ,Thrombotic microangiopathy ,Genotype ,ADAMTS13 Protein ,030204 cardiovascular system & hematology ,Young Adult ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Untranslated Regions ,hemic and lymphatic diseases ,Genetic predisposition ,Humans ,Transplantation, Homologous ,Medicine ,Genetic Predisposition to Disease ,Clinical significance ,Gene ,Aged ,Genome ,Thrombotic Microangiopathies ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,ADAMTS13 ,Transplantation ,030104 developmental biology ,Hematologic Neoplasms ,RNA splicing ,Immunology ,Female ,business - Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that pretransplant genetic susceptibility is evident in adult TA-TMA and further investigated the association of TMA-associated variants with clinical outcomes. We studied 40 patients with TA-TMA, donors of 18 patients and 40 control non-TMA HCT recipients, without significant differences in transplant characteristics. Genomic DNA from pretransplant peripheral blood was sequenced for TMA-associated genes. Donors presented significantly lower frequency of rare variants and variants in exonic/splicing/untranslated region (UTR) regions, compared with TA-TMA patients. Controls also showed a significantly lower frequency of rare variants in ADAMTS13, CD46, CFH, and CFI. The majority of TA-TMA patients (31/40) presented with pathogenic or likely pathogenic variants. Patients refractory to conventional treatment (62%) and patients that succumbed to transplant-related mortality (65%) were significantly enriched for variants in exonic/splicing/UTR regions. In conclusion, increased incidence of pathogenic, rare and variants in exonic/splicing/UTR regions of TA-TMA patients suggests genetic susceptibility not evident in controls or donors. Notably, variants in exonic/splicing/UTR regions were associated with poor response and survival. Therefore, pretransplant genomic screening may be useful to intensify monitoring and early intervention in patients at high risk for TA-TMA.
- Published
- 2020