SPARCL1 – Corneal Dystrophy

This summary describes the association between SPARCL1 and corneal dystrophy. The evidence is derived from a well‐characterized pedigree that demonstrated an autosomal dominant pattern of inheritance, with eight affected individuals spanning three generations (PMID:39169229). The affected individuals presented with diffuse central stromal opacity and reduced visual acuity, underscoring the clinical significance of the findings. Segregation analysis confirmed that the identified missense variant was present in all affected family members, and no other variants in established corneal dystrophy genes were found. This robust segregation supports the causative relationship between the SPARCL1 variant and the corneal dystrophy phenotype.

The genetic evidence is anchored by the identification of a heterozygous missense variant, c.334G>A (p.Glu112Lys), which co-segregates with the disease in this pedigree (PMID:39169229). This variant was detected through whole genome sequencing and was absent in population databases, further reinforcing its pathogenic relevance. The variant affects a highly conserved residue in SPARCL1, and multiple in silico predictions support a damaging effect on protein function. Such evidence satisfies key criteria for pathogenicity and provides strong support for the role of SPARCL1 in corneal dystrophy.

In addition to the genetic data, functional studies complement the association by demonstrating molecular alterations relevant to the disease mechanism. Immunohistochemical analysis of affected corneal tissue revealed significantly reduced decorin levels, a protein known to interact with SPARCL1 and implicated in corneal structure maintenance (PMID:39169229). This finding is consistent with the hypothesis that the SPARCL1 missense variant disrupts normal protein function, ultimately leading to impaired stromal integrity. The loss of decorin parallels the known mechanism seen in decorin-related corneal dystrophies, thereby lending biological plausibility to the genetic findings.

The convergence of genetic results with supportive functional data establishes a strong association between the SPARCL1 variant and corneal dystrophy. Despite the phenotypic heterogeneity seen in corneal dystrophies, this study provides clear evidence by fulfilling multiple ClinGen criteria, including segregation, rarity of the variant, and concordant functional impact. The pathogenic mechanism appears to be mediated through altered protein interactions and extracellular matrix remodeling, which are critical for corneal transparency. These insights significantly contribute to diagnostic decision-making and may guide the development of targeted interventions.

Further supporting evidence from multi-patient studies reiterates the importance of this variant in disease pathogenesis. Although additional studies in independent cohorts are warranted, the current evidence exceeds the threshold for a strong gene-disease association. The replication of key findings across case reports and multi-patient studies underlines the robustness of the association and supports its clinical validity. This comprehensive dataset is invaluable for both commercial genetic testing and future research publications.

In summary, the association between SPARCL1 and corneal dystrophy is underpinned by robust genetic, segregation, and experimental evidence. The identification of the c.334G>A (p.Glu112Lys) variant that segregates with the phenotype, combined with supportive functional data, reinforces the pathogenic relationship. This integrated evidence base provides clinicians with a reliable foundation for diagnostic evaluation and underscores the practical utility of genetic testing in corneal dystrophy cases. The key take‑home message is that a rigorous analysis of both genetic and functional evidence confirms SPARCL1 as a causative gene for autosomal dominant corneal dystrophy.

References

• European journal of human genetics : EJHG • 2024 • Autosomal dominant stromal corneal dystrophy associated with a SPARCL1 missense variant PMID:39169229

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