TMEM98 – Nanophthalmos

TMEM98 has emerged as a critical gene underlying nanophthalmos, a congenital disorder characterized by reduced axial length, high hyperopia, and complications such as angle-closure glaucoma. In a landmark study, a large white kindred with autosomal dominant nanophthalmos was rigorously evaluated, revealing that 16 individuals exhibited the phenotype with significantly short axial lengths and high refractive errors (PMID:24852644). This investigation provided robust evidence through clinical assessment and genome-wide analyses that linked TMEM98 variants directly to the disease phenotype.

Further supporting the genetic association, a multi-patient study identified a deleterious TMEM98 variant that co-segregated with nanophthalmos in an independent cohort, reinforcing the autosomal dominant inheritance pattern. In that study, the variant was seen in a family with four affected members along with additional independent cases, thereby broadening the clinical spectrum and establishing its recurrent nature (PMID:33203948). Such replication across distinct cohorts elevates the clinical validity of TMEM98 in nanophthalmos diagnosis.

Genetic evidence is bolstered by the identification of a specific missense variant, c.577G>C (p.Ala193Pro), found in exon 8 of TMEM98. This variant was absent in control populations, segregated with the disease in the affected kindred, and meets the rigorous criteria established by ClinGen for pathogenicity. Its recurrence in independent studies provides compelling support for its role as a disease-causing variant in nanophthalmos (PMID:24852644; PMID:33203948).

The functional impact of TMEM98 variants has been directly addressed by CRISPR/Cas9 mutagenesis studies in mice. The recreation of the human c.577G>C (p.Ala193Pro) variant in mice recapitulated key ocular phenotypes, including the appearance of discrete white spots on the retinal fundus and histological retinal folds, mirroring human disease features (PMID:37419942). These functional assays underscore the gene’s role in maintaining normal ocular structure and support a pathogenic mechanism likely involving disruption of protein function critical for eye development.

Integration of the clinical, genetic, and functional data provides a coherent narrative that strongly implicates TMEM98 in autosomal dominant nanophthalmos. The evidence spans a large family study with significant segregation, replication in independent cohorts, and corroborative functional studies using an animal model. This comprehensive dataset not only supports the clinical utility of TMEM98 testing in diagnostic decision-making but also opens avenues for targeted therapeutic interventions.

Key take‑home sentence: The strong association of TMEM98 with autosomal dominant nanophthalmos, established through rigorous clinical, genetic, and functional evidence, makes it a highly relevant target for diagnostic and translational applications.

References

• JAMA Ophthalmology • 2014 • Mutation in TMEM98 in a large white kindred with autosomal dominant nanophthalmos linked to 17p12-q12 PMID:24852644
• Scientific Reports • 2020 • Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort PMID:33203948
• Scientific Reports • 2023 • Phenotypic consequences of a nanophthalmos-associated TMEM98 variant in human and mouse PMID:37419942

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