BACKGROUND: Corneal intraepithelial dyskeratosis is an extremely rare condition. 
The classical form, affecting Native American Haliwa-Saponi tribe members, is 
called hereditary benign intraepithelial dyskeratosis (HBID). Herein, we present 
a new form of corneal intraepithelial dyskeratosis for which we identified the 
causative gene by using deep sequencing technology.
METHODS AND RESULTS: A seven member Caucasian French family with two corneal 
intraepithelial dyskeratosis affected individuals (6-year-old proband and his 
mother) was ascertained. The proband presented with bilateral complete corneal 
opacification and dyskeratosis. Palmoplantar hyperkeratosis and laryngeal 
dyskeratosis were associated with the phenotype. Histopathology studies of 
cornea and vocal cord biopsies showed dyskeratotic keratinisation. Quantitative 
PCR ruled out 4q35 duplication, classically described in HBID cases. Next 
generation sequencing with mean coverage of 50× using the Illumina Hi Seq and 
whole exome capture processing was performed. Sequence reads were aligned, and 
screened for single nucleotide variants and insertion/deletion calls. In-house 
pipeline filtering analyses and comparisons with available databases were 
performed. A novel missense mutation M77T was discovered for the gene NLRP1 
which maps to chromosome 17p13.2. This was a de novo mutation in the proband's 
mother, following segregation in the family, and not found in 738 control DNA 
samples. NLRP1 expression was determined in adult corneal epithelium. The amino 
acid change was found to destabilise significantly the protein structure.
CONCLUSIONS: We describe a new corneal intraepithelial dyskeratosis and how we 
identified its causative gene. The NLRP1 gene product is implicated in 
inflammation, autoimmune disorders, and caspase mediated apoptosis. NLRP1 
polymorphisms are associated with various diseases.