Complement-related genetic analysis for Japanese children with transplant-associated thrombotic microangiopathy

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Previous reports in the United States have suggested that TA-TMA is caused by complement-related genetic variants. However, these findings need to be validated in other countries and ethnic populations.

We performed targeted sequencing of 40 complement-and coagulopathy-related genes in 44 Japanese pediatric patients who underwent HSCT, including 20 patients with TA-TMA and 24 patients without TA-TMA. Seventeen genes reported to be related to TA-TMA were included. Additionally, 23 genes that are thought to be associated with complement system activation and coagulopathy were investigated. CFHR1/CFHR3 deletions were also examined using multiplex ligation-dependent probe amplification.

There was no significant difference in the percentage of patients bearing genetic variants between patients with and without TA-TMA. Furthermore, no marked differences in the percentage of patients or the average number of rare variants per patient were found between the two groups. Although we identified several rare non-synonymous variants in TA-TMA patients, we did not find any known pathogenic variants causing TA-TMA. Interestingly, a novel rare genetic variant in the C1r-like protein (C1RL) gene was identified in a patient with neuroblastoma who had undergone autologous HSCT, potentially associated with TA-TMA.

In this limited number of Japanese pediatric cohort with TA-TMA, we could not find an enrichment of rare variants among 40 complement- and coagulopathy-related genes. A novel, rare variant of C1RL was identified in a single patient with TA-TMA. Further studies with larger cohorts are necessary to clarify the genetic association in Japanese patients with TA-TMA.