TSEN2 – Atypical Hemolytic‑Uremic Syndrome

This summary integrates evidence from multiple studies that associate TSEN2 (HGNC:28422) with atypical hemolytic‑uremic syndrome (aHUS) (MONDO_0016244). Two independent lines of evidence are presented. First, a case report of a 4‑year‑old girl with a clinical presentation of hemolytic anemia, thrombocytopenia, and renal insufficiency demonstrated a TSEN2 mutation and an unresponsive course to plasma exchange (PMID:37338178). Second, a multi‐patient study identified a recurrent autosomal recessive TSEN2 mutation in six individuals from four consanguineous families. Affected individuals not only presented with aHUS, including features such as proteinuria and microangiopathic hemolytic anemia, but also had associated craniofacial and central nervous system malformations (PMID:34964109).

The genetic evidence strongly supports an autosomal recessive mode of inheritance. In the multi‐patient study, segregation analysis within consanguineous families pointed to the recurrence of pathogenic variants and highlighted abnormal splicing events affecting TSEN2. The reported variant, c.23C>A (p.Ala8Asp), is noted as a recurrent mutation in affected individuals (PMID:34964109). This variant was selected from the mutation list after careful review of the evidence and meets all criteria for complete coding change following HGVS nomenclature.

Functional studies further reinforce the genetic findings. Experimental assessments, including morpholino‑mediated skipping of exon 10 in a zebrafish model, produced phenotypes that recapitulate key elements of the clinical picture in aHUS. Abnormal tRNA transcripts observed in peripheral blood cells also support the hypothesis of a pathogenic mechanism linking TSEN2 dysfunction to vascular endothelial instability. Although detailed functional study findings are summarized briefly here, they align with the clinical observations and support the role of TSEN2 mutations in disease pathogenesis.

The convergence of genetic and experimental evidence underscores a strong association between TSEN2 and aHUS. Despite the presence of additional phenotypes, such as craniofacial malformations in certain individuals, the aHUS phenotype remains a consistent and defining clinical element in both studies. This multi‐facet evidence, drawn from both isolated case reports and family-based studies, enhances the confidence in the gene‑disease relationship.

In summary, the combined data—including traditional case evidence, segregation analysis in multiple families, and supportive functional experiments—supports the clinical validity of TSEN2 as a strong contributor to the pathogenesis of atypical hemolytic‑uremic syndrome. Clinicians can leverage this information in diagnostic decision‑making and as a foundation for translational research, despite the complexity introduced by additional overlapping clinical features.

Key Take‑Home: The robust association between TSEN2 and aHUS, highlighted by consistent genetic and functional evidence, provides critical insights for clinical diagnosis and personalized therapeutic strategies.

References

• Journal of clinical apheresis • 2023 • Why has plasma exchange failed in TRACK syndrome? Lessons from a new variant of the atypical hemolytic uremic syndrome. PMID:37338178
• Clinical genetics • 2022 • A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome. PMID:34964109

Evidence Based Scoring (AI generated)