LADD syndrome with glaucoma is caused by a novel gene.

PURPOSE

Lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal dominant disorder displaying variable expression of multiple congenital anomalies including hypoplasia or aplasia of the lacrimal and salivary systems causing abnormal tearing and dry mouth. Mutations in the , , and 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

Whole exome sequencing was performed, and previously described disease-causing genes ( and ) 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

No mutations were detected in , , or . The LADD syndrome patient's exome data was searched for mutations in the 58 candidate genes and only one mutation was detected, an Arg343Trp mutation in the tumor protein 63 () gene. This 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

We report a patient with no mutations in known LADD syndrome genes (, , and ). Our analysis provides strong evidence that the Arg343Trp mutation in caused LADD syndrome in our patient and that is a fourth gene contributing to this condition. encodes a transcription factor involved in the development and differentiation of tissues affected by LADD syndrome. These data suggest that is a novel LADD syndrome gene and may also influence corneal thickness and risk for open-angle glaucoma.