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

Abstract

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.

A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis)

“…Despite strikingly similar clinical aspects of the skin and the corneal dyskeratosis and dental problems for patient 3, the patients we describe presented a more complex phenotype characterised by a unique combination of features, namely recurrent fever with elevated biological markers of inflammation, arthritis initially classified as sJIA in family 1, intraepithelial dyskeratosis, vitamin A deficiency, slight autoimmunity and high transitional B-cell count in two of the three patients. The similar dermatological manifestations between our patients and those described by Soler et al ,23 as well as the genetic susceptibility of NLRP1 in skin disorders such as vitiligo10 and psoriasis,24 suggest that NLRP1 may have a unknown role in skin innate immune responses.…”

“…The domain structure of the NLRP1 protein is represented (NM_033004.3; NP_12749.1). The figure shows the location of the mutations identified in this manuscript (p.Arg726Trp and p.Pro1214Arg) and in isolated corneal intraepithelial dyskeratosis (p.Met77Thr)23 (red arrows). CARD, caspase recruitment domain; FIIND, function to find domain; LRR, leucine-rich repeat domain; PYD, pyrin domain; NACHT domain (neuronal apoptosis inhibitor protein, major histocompatibility class 2 transcription activator, incompatibility locus protein from Podospora anserine and telomerase-associated protein).…”

“…The mutation is associated with a dominant disorder with isolated corneal intraepithelial hyperplasia with dyskeratosis and parakeratosis 23. Despite strikingly similar clinical aspects of the skin and the corneal dyskeratosis and dental problems for patient 3, the patients we describe presented a more complex phenotype characterised by a unique combination of features, namely recurrent fever with elevated biological markers of inflammation, arthritis initially classified as sJIA in family 1, intraepithelial dyskeratosis, vitamin A deficiency, slight autoimmunity and high transitional B-cell count in two of the three patients.…”

Hereditary Benign Intraepithelial Dyskeratosis: Report of a Case and Re-examination of the Evidence for Locus Heterogeneity

“…In cases in which the conjunctival epithelial abnormalities extend onto the cornea, vision may be affected and corneal transplantation may be required. 1, 2 While HBID was originally described in members of the Haliwa-Saponi Native American tribe located in North Carolina 3 , and the majority of the reports of HBID have been in this population, 4–11 six other pedigrees without Native American ancestry, consisting of between 1 and 4 affected individuals in each, have been reported. 1, 2, 12–15 …”

“…Recently, another group has reported a Caucasian French family with histopathologically-confirmed HBID in whom quantitative PCR (qPCR) excluded a 4q35 duplication. 2 Next generation sequencing identified an unreported, novel missense mutation in the NLRP1 gene on chromosome 17 in the affected proband and his affected mother that was predicted to destabilize the encoded protein. However, screening of NLRP1 in Native Americans from 3 families with HBID failed to reveal a pathogenic mutation.…”