LADD syndrome with glaucoma is caused by a novel gene.

Abstract

PURPOSE: genes were found to cause some cases of LADD syndrome in prior genetic studies. The goal of this study is to identify the genetic basis of a case of LADD syndrome with glaucoma and thin central corneal thickness (CCT). METHODS: ) were first evaluated for mutations. Fifty-eight additional prioritized candidate genes were identified by searching gene annotations for features of LADD syndrome. The potential pathogenicity of the identified mutations was assessed by determining their frequency in large public exome databases; through sequence analysis using the Blosum62 matrix, PolyPhen2, and SIFT algorithms; and through homology analyses. A structural analysis of the effects of the top candidate mutation in tumor protein 63 (TP63) was also conducted by superimposing the mutation over the solved crystal structure. RESULTS: mutation is absent from the gnomAD sequence database. Analysis of the Arg343Trp mutation with Blosum62, PolyPhen2, and SIFT all suggest it is pathogenic. This arginine residue is highly conserved in orthologous genes. Finally, crystal structure analysis showed that the Arg343Trp mutation causes a significant alteration in the structure of TP63's DNA binding domain. CONCLUSIONS: is a novel LADD syndrome gene and may also influence corneal thickness and risk for open-angle glaucoma.