NGS in hematopoietic cell transplant recipients

ABSTRACT: Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that pre-transplant genetic susceptibility is evident in adult TA-TMA patients at the level of TMA-associated variants and further investigated the association of genetic variants with clinical outcomes. We studied 30 patients with TA-TMA at a median of 73 (9-540) post-transplant days, donors of 18/30 patients and 30 control non-TMA HCT recipients, without significant differences in transplant characteristics. Genomic DNA from pre-transplant peripheral blood was analyzed by targeted next generation sequencing for complement regulatory genes and ADAMTS13. Donors presented significantly lower frequency of rare variants (p=0.049) and variants in exonic/splicing/UTR regions (p=0.025), compared to TA-TMA patients. Controls also showed a significantly lower frequency of rare variants in ADAMTS13 (p=0.001), CD46 (p=0.002), CFH (p=0.010) and CFI (p=0.031). Pathogenic variants were found in ADAMTS13, CFH, CFI and CFB, while homozygous pathogenic variants in ADAMTS13 and CFB were evident in only 4 TA-TMA patients (p=0.038). Patients refractory to conventional treatment (70%) were significantly (p=0.045) enriched for variants in exonic/splicing/UTR regions compared to responders. Nineteen of 30 patients (63%) succumbed to transplant-related mortality, which was also associated with significantly (p=0.012) increased frequency of 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, pre-transplant genomic screening may be useful to intensify monitoring and early intervention in high-risk patients.

INSTRUMENT(S): MiniSeq, Illumina MiniSeq

ORGANISM(S): Homo sapiens

SUBMITTER: Eleni Gavriilaki 

PROVIDER: E-MTAB-7848 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress