A novel autosomal dominant Corneal Stromal Dystrophy associated with a SPARCL1 missense variant

Abstract

Purpose : To investigate the genetic cause of a corneal dystrophy (CD) characterised by progressive and painless stromal opacification.

Methods : We recruited a three-generation pedigree comprising five individuals affected with corneal opacity displaying an autosomal dominant inheritance pattern. DNA was available from eight family members: five affected and three unaffected. In three of the affected individuals, we performed whole genome sequencing (WGS) and annotated with ANNOVAR (GRCh37). WGS data was filtered for shared variants with a MAF<0.001 (gnomAD v2.1.1). Verification and segregation analyses were performed for candidate variants on all samples. Qualifying variants were assessed for biological significance, expression in relevant corneal cells and tissue, and their predicted pathogenicity. Immunohistochemistry (IHC) was performed to localise SPARCL1 within a control full thickness human cornea.

Results : Affected individuals showed a diffuse central corneal stromal opacity associated with a reduced visual acuity in older family members (>50 years). There were no other ocular or systemic abnormalities. No rare potentially pathogenic variants were identified in established CD-associated genes. A novel heterozygous SNV in exon 4 of SPARCL1 c.334G>A; p.(Glu112Lys), with a MAF frequency of 0, was subsequently confirmed to fully segregate with disease in the extended family. This variant is predicted to exert a detrimental effect on protein function (SIFT = 0.00). SPARCL1 encodes SPARC-like protein 1 (SPARCL1), also termed Hevin, an extracellular matrix, collagen-binding protein with a role in tissue repair and remodelling, which is highly expressed in the cornea. IHC staining confirmed expression in the intracellular spaces of the corneal stroma. Interestingly, hevin (-/-) knockout mice develop corneal haze and decorin levels are reduced in the dermis. Heterozygous variants in the Decorin-encoding gene, DCN, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway.

Conclusions : We report a novel variant in SPARCL1 that we hypothesise is associated with dominantly inherited corneal opacity, extending the phenotypic and genetic heterogeneity of inherited corneal disease. Further investigation of the role of SPARCL1 in corneal homeostasis is warranted.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.