HECTD1 – Neural Tube Defects

In a targeted sequencing study of 352 Neural Tube Defect cases PMID:38260607 and 224 matched controls, five rare heterozygous HECTD1 missense variants (p.Met392Val, p.Thr801Ile, p.Ile906Val, p.Ala1084Thr, and p.Pro1835Leu) were identified exclusively in unrelated probands [PMID:38260607; PMID:38451291]. No segregation data or unaffected carriers have been reported, limiting the genetic evidence to case series observations.

HECTD1 is a HECT-domain E3 ubiquitin ligase essential for cranial neural tube closure in mouse models via regulation of cranial mesenchyme morphogenesis. Functional assays in HEK293T cells showed that all five NTD-associated variants impaired suppression of extracellular HSP90 secretion, and c.3250G>A (p.Ala1084Thr) also exhibited reduced protein expression [PMID:38260607; PMID:38451291]. These concordant cellular data support a hypomorphic mechanism of pathogenicity.

Overall, the evidence for a HECTD1–neural tube defect association is classified as Limited owing to case-level variant observations without segregation or replication in independent cohorts. Further family studies and replication are required to establish causality. Key Take-home: HECTD1 missense variants may contribute to NTD risk and warrant inclusion in diagnostic gene panels.

References

• Research square • 2024 • Identification and Functional Analysis of Rare HECTD1 Missense Variants in Human Neural Tube Defects. PMID:38260607
• Human genetics • 2024 • Identification and functional analysis of rare HECTD1 missense variants in human neural tube defects. PMID:38451291

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