Biallelic pathogenic variants in EXOSC3 mediate renal thrombotic microangiopathy of the kidney.

Biallelic rare variants in EXOSC3, a component of the RNA exosome; in a tamoxifen-inducible whole-body Exosc3 conditional knockout mouse, cell cycle arrest and apoptosis affecting actively dividing cells (bone marrow, large intestine), without identifiable kidney pathology in that time frame.

The authors assembled 34 children across Europe carrying rare EXOSC3 variants causing pontocerebellar hypoplasia type 1b and reviewed their clinical history for signs of thrombotic microangiopathy. Thirteen cases of EXOSC3-related thrombotic microangiopathy were identified (eight male, five female), with an estimated UK incidence of 0.004 per million per year. Three children received long-term eculizumab: one failed to respond and two relapsed on treatment. The inducible conditional knockout mouse showed cell cycle arrest and apoptosis in actively dividing cells, with death at a median of eight days and no kidney pathology detected in that time frame. The authors conclude this is a severe, early-onset, C5 inhibitor-resistant thrombotic microangiopathy.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A direct, actionable clinical message: in paediatric thrombotic microangiopathy resistant to eculizumab, particularly alongside neurodevelopmental disease, EXOSC3 should be considered — which avoids persisting with ineffective complement inhibition. The series is retrospective and the mouse model, dying within eight days, does not reproduce the renal phenotype, so pathogenesis remains unresolved. Its main value is as a phenotype-recognition signal for clinical geneticists and paediatric nephrologists.

Analysis by Dr Thibaut Benquey