RT Journal Article
SR Electronic
T1 Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 246
OP 254
DO 10.1136/jmedgenet-2012-101325
VO 50
IS 4
A1 Vincent José Soler
A1 Khanh-Nhat Tran-Viet
A1 Stéphane D Galiacy
A1 Vachiranee Limviphuvadh
A1 Thomas Patrick Klemm
A1 Elizabeth St Germain
A1 Pierre R Fournié
A1 Céline Guillaud
A1 Sebastian Maurer-Stroh
A1 Felicia Hawthorne
A1 Cyrielle Suarez
A1 Bernadette Kantelip
A1 Natalie A Afshari
A1 Isabelle Creveaux
A1 Xiaoyan Luo
A1 Weihua Meng
A1 Patrick Calvas
A1 Myriam Cassagne
A1 Jean-Louis Arné
A1 Steven G Rozen
A1 François Malecaze
A1 Terri L Young
YR 2013
UL http://jmg.bmj.com/content/50/4/246.abstract
AB 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.