An assessment of GUCA1C variants in primary congenital glaucoma

In the special issue “Molecular Genetics of Retinal Dystrophies”, Morales–Cámara and colleagues reported the association of a new candidate gene with primary congenital glaucoma (PCG). They identified a low-frequency nonsense homozygous variant (p.(Glu18Ter)) in the GUCA1C gene in two affected siblings with proposed autosomal recessive inheritance. Immunohistochemistry showed the presence of the encoded protein GCAP3 in human ocular tissues, including the ciliary epithelium and the retina. Additionally, the authors developed a guca1c knockout zebrafish and reported evidence of retinal ganglion cell apoptosis and the presence of GCAP3 in the same ocular tissues in adult wild-type zebrafish as in humans.
As previously reported by the ClinGen Gene Curation Working Group, the clinical validity of a gene–disease relationship can be assessed based on the strength of evidence that includes both genetic evidence (such as case-control studies or segregation data), and experimental evidence [2]. Here we aimed to investigate additional evidence regarding the reported association between GUCA1C variants and PCG.
In an effort to replicate these findings, we screened GUCA1C for variants in two separate cohorts of individuals with PCG, all predominantly of self-reported European ancestry.