PURPOSE:The purpose of this study was to investigate the clinical and genetic features of a man and his daughter with posterior polymorphous corneal dystrophy (PPCD), referred to our clinic for Descemet membrane endothelial keratoplasty. No other known relatives were affected.METHODS:Ophthalmic examination and histology, including electron microscopy, were performed. Genetic testing was conducted by means of whole exome sequencing, and variant analysis was achieved by using an internal in silico pipeline. Molecular tests included a dual-luciferase assay.RESULTS:Slowly progressive blurred vision was reported from childhood by the daughter. The father's symptoms started at age 55. Best-corrected visual acuity was reduced in both patients (0.2-0.4). Slit-lamp examination in both patients revealed bilateral corneal clouding with gray endothelial lesions; other family members had no ophthalmological signs. Descemet membrane endothelial keratoplasty was performed uneventfully in both patients. Histology showed thickened Descemet membrane and abnormal endothelium resembling epithelial-like cells. Both patients carried the OVOL2 5' untranslated region NM_021220.4.c.-61G>A variant in the heterozygous state. This change was associated with increased promoter activity and was not present in the unaffected members of the family.CONCLUSIONS:The 5' untranslated region mutation c.-61G>A in OVOL2 has been previously found in 1 individual with PPCD1 and reported as a variant of unknown significance because of insufficient evidence supporting its pathogenicity. Identification of the second family with 2 individuals affected by PPCD1 carrying this change, together with functional data, provides further proofs that it is disease-causing.

To investigate the clinical and genetic features of a man and his daughter with Posterior polymorphous corneal dystrophy 1 (PPCD1), referred to our clinic for Descemet's Membrane Endothelial Keratoplasty (DMEK). No other known relatives were affected, including the index patient's spouse and their son. Clinical examination was performed by best-corrected visual acuity (BCVA) testing, slit-lamp examination (SLE), anterior-segment optical coherency tomography (OCT) and specular microscopy. Histologic testing and electron microscopy were done. Genetic testing was carried out by means of Whole-Exome Sequencing (WES), and variant analysis was achieved by an internal in silico pipeline. Slowly progressive blurred vision was reported from childhood by the daughter. The father's symptoms started approximately ten years prior to consultation. BCVA was 0.2 in both eyes in the father and 0.2/0.4 in the right/left eye in the daughter. SLE in both patients revealed bilateral corneal clouding with focal grey endothelial spots. Corneal edema with Descemet's folds was present. DMEK was performed uneventfully. Histology and electron microscopy showed layered Descemet's membrane and pleomorphic endothelial cells with vacuoles but no microvilli. Genetic analysis revealed the c. -61G>A variant in the 5′UTR region of the OVOL2 gene heterozygously, in both patients. This change was not present in the unaffected members of the family. PPCD1 has been linked to mutations in the promoter and the 5′UTR region of OVOL2 . The NM_021220.4:c.-61G>A DNA change was previously reported as a variant of unknown pathogenicity, despite having been identified in another patient with PPCD1. Based on perfect familial co-segregation, complete absence of this change in all public databases of normal controls, and its identification in two additional individuals with PPCD1, we conclude that c.-61G>A is a truly pathogenic mutation for this condition.