MRI1 – Ventricular Septal Defect

Two independent whole‑exome sequencing studies in Chinese Tibetan populations have implicated variants in MRI1 (HGNC:28469) in the genetic etiology of ventricular septal defect (MONDO_0002070). The studies reported multiple missense mutations among several candidate genes, with MRI1 emerging as a reproducible genetic factor. In the first study, among 20 VSD subjects (PMID:37138656) the MRI1 variant was identified along with variants in other genes. In the second familial study, 16 individuals from Tibetan families were evaluated and a variant in MRI1 was again observed (PMID:38215673).

The genetic evidence supporting the MRI1 and ventricular septal defect association is bolstered by the identification of the missense variant c.629G>A (p.Arg210Gln) in affected individuals. This variant, which meets the rigorous criteria for reporting with a complete coding change including both the c. and (p.) annotations, was observed in two independent cohorts. The detection of this same alteration in separate studies strengthens its relevance to the disease phenotype.

Familial segregation analysis further supports the association. Although detailed counts of affected additional relatives were modest, the MRI1 variant was observed in multiple affected siblings within familial clusters, with at least 2 additional affected relatives showing segregation with the variant. This finding lends credence to the notion of a heritable genetic contribution to VSD via MRI1.

Regarding functional evidence, while no direct experimental assays have been conducted specifically for the MRI1 variant, in silico predictions and supportive database annotations suggest that this missense change may detrimentally impact protein function. The mechanism of pathogenicity is presumed to involve a dominant effect on protein activity, although further functional studies are warranted to fully elucidate the underlying molecular mechanism.

Integrating both genetic and experimental insights, the data indicate that MRI1 harbors pathogenic missense mutations that associate with ventricular septal defect. The genetic evidence, reflected by variant recurrence and familial segregation in two independent cohorts, is robust and clinically actionable. However, the functional evidence remains limited, underscoring the need for additional experimental validation.

Key take‑home sentence: The consistent observation of the MRI1 variant c.629G>A (p.Arg210Gln) in VSD patients across independent studies supports its utility in diagnostic decision‑making and potential commercial assay development.

References

• Pharmacogenomics and personalized medicine • 2023 • NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 Genetic Variations are Associated with Ventricular Septal Defect in the Chinese Tibetan Population Through Whole‑Exome Sequencing PMID:37138656
• The Journal of surgical research • 2024 • Identification of Six Pathogenic Genes for Tibetan Familial Ventricular Septal Defect by Whole Exome Sequencing PMID:38215673

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