HS3ST6 – Hereditary Angioedema

Hereditary angioedema (HAE) is a serious, potentially life‑threatening disorder that is most commonly inherited in an autosomal dominant manner. Recent multi‑patient studies have expanded the genetic heterogeneity of HAE to include HS3ST6, alongside more well‑established genes. These studies reported cohorts from diverse populations, including a Saudi Arabian study with 51 patients from 17 unrelated families (PMID:36348183) and a complementary report detailing the expanding mutation spectrum in HAE (PMID:33746090).

Genetic evidence for HS3ST6 has emerged from family‐based analyses where a mutation was identified in a multi‑generational pedigree. Specifically, whole exome sequencing revealed the variant c.430A>T (p.Thr144Ser), which segregated in three affected family members (PMID:33508266). The segregation data, although derived from a limited number of individuals, contributes to the overall support for the association.

In-depth functional studies have provided mechanistic insights into how the HS3ST6 variant disrupts the normal biosynthetic pathway of heparan sulfate (HS). Biochemical assays in the affected family showed that the p.Thr144Ser change adversely impacts the active center of the HS‑glucosamine 3‑O‑sulfotransferase 6 enzyme, leading to defective HS biosynthesis. This loss of function is consistent with abnormal cell surface interactions implicated in angioedema formation (PMID:33508266).

While the majority of HAE cases are linked to anomalies in SERPING1 and F12, the inclusion of HS3ST6 in recent genomic screens supports its role in a subset of patients, particularly those with normal C1‑inhibitor profiles. No studies to date have presented conflicting evidence regarding the involvement of HS3ST6 in HAE, and the functional data cement the biological plausibility of its contribution to disease pathogenesis.

Overall, the convergence of multi‑patient genetic findings and robust functional evidence substantiates a moderate level of clinical validity for the association between HS3ST6 and hereditary angioedema. The identification and mechanistic validation of the c.430A>T (p.Thr144Ser) variant enrich the current understanding of HAE pathogenesis and underscore the importance of incorporating HS3ST6 into genetic diagnostic panels.

Key take‑home sentence: Incorporating HS3ST6 genetic analysis into the diagnostic workflow for hereditary angioedema can enhance precision in patient care and inform targeted therapy decisions.

References

• Journal of clinical immunology • 2023 • Phenotypic and Genotypic Characterization of Hereditary Angioedema in Saudi Arabia PMID:36348183
• The journal of allergy and clinical immunology. In practice • 2021 • The Expanding Spectrum of Mutations in Hereditary Angioedema PMID:33746090
• The Journal of allergy and clinical immunology • 2021 • Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation PMID:33508266

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