Abstract
Purpose :
Posterior polymorphous corneal dystrophy (PPCD) is a rare, autosomal dominant condition caused by pathogenic variants in three genes ZEB1 (PPCD3), OVOL2 (PPCD1), and GRHL2 (PPCD4). The global prevalence of PPCD is unknown. Epidemiological data in well-defined populations may provide a good approximation of the true prevalence of the claimed orphan condition. While OVOL2- and GRHL2-associated disease is attributed to gain-of-function regulatory mutations with strong founder effects in some populations, PPCD3 is caused by loss-of-function ZEB1 variants identified worldwide. The aim of this study was to report on the prevalence of molecularly confirmed PPCD3 in the Czech Republic.
Methods :
All patients diagnosed with PPCD3 in the Czech Republic, up until December 2022, were evaluated. Genetically unresolved probands were subjected to exome sequencing. Detected pathogenic/likely pathogenic variants were verified by Sanger sequencing, which was also used for familial segregation analysis.
Results :
In total, 38 individuals from 17 white Czech families with PPCD3 have been ascertained, of these one individual showed non-penetrance for the phenotype and in one family member detailed ocular examination is pending. All but one family was identified to carry unique ZEB1 pathogenic variants, five of which have been previously unreported; NM_030751.6: c.685-1G>A, c.753C>G, c.984dup, c.1060G>T, c.2858T>G. Sequencing of available first-degree relatives showed that the pathogenic variants occurred de novo in at least 5 (29%) families. As three PPCD3 cases have deceased, including the asymptomatic carrier, the total number of living affected individuals with PPCD3 in the Czech Republic is at least 35.
Conclusions :
Given the intensive PPCD screening approaches adopted by the Czech Republic, which has 10.7 million inhabitants, we suggest that 1/306,000 represents the most accurate prevalence figure for PPCD3 estimated to date. However, as individuals with PPCD3-causing variants can remain asymptomatic, the true figure is hypothesised to be higher. The total number of reported PPCD3-associated variants worldwide is currently 56, and of these a significant proportion (n=16; 29%), has been identified in the Czech patient population. Our study also shows that ZEB1 loss-of-function mutations occur de novo in about one-third of PPCD3 families.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.