Whole exome sequencing identifies a mutation for a novel form of hereditary benign intraepithelial dyskeratosis

Purpose To identify a gene for a novel, autosomal dominant form of hereditary benign intraepithelial dyskeratosis (HBID) in a Caucasian French pedigree using deep sequencing technology. Methods A 7-member family with two affected individuals (6-year-old proband and his mother) with corneal lesions was ascertained. The proband presented with bilateral complete corneal opacification with dyskeratosis, and circumferential corneolimbal neovascularization. Cutaneous features of palmoplantar hyperkeratosis as well as laryngeal dyskeratosis were associated with the ocular phenotype. Histopathology studies of cornea and vocal chord biopsies showed dyskeratotic keratinization. Next generation sequencing with mean coverage of 50x using the Illumina Hi Seq and whole exome capture processing was performed. Sequence reads were aligned, and screened for single nucleotide variant and insertion/deletion calls. In-house pipeline filtering analyses and comparisons with public databases were performed. cDNA expression studies were conducted using systemic and ocular tissues. Results A novel missense mutation M77T was discovered for the gene NLRP1 which maps to chromosome 17p13.2. This mutation was de novo in the proband’s mother, followed segregation in the family, and was not found in 800 control DNA samples. NLRP1 expression was determined in adult cornea. Conclusion A de novo mutation in NLRP1 segregated with HBID in a non-Native American family. The gene product is implicated in inflammation, autoimmune disorders, and caspase-mediated apoptosis. This is the first identification of a causative gene for a form of autosomal dominant HBID.