title: Application of whole exome sequencing in elucidating the phenotype and genotype spectrum of junctional epidermolysis bullosa: A preliminary experience of a tertiary care centre in India.
abstract: BACKGROUND
  Junctional epidermolysis bullosa (JEB) is a diverse group of genodermatoses associated with extreme skin fragility. Despite several well-characterized genetic studies, molecular diagnosis of this heterogeneous group is still challenging. Recent advances in the field of genomics have seen the successful implementation of whole exome sequencing (WES) as a fast and efficient diagnostic strategy in several genodermatoses.
  
  
  OBJECTIVE
  In view of the scarcity and need of molecular studies for JEB in India, we sought to explore the potential of WES in understanding the mutational spectrum of this rare, in certain subtypes lethal, sub-group of EB.
  
  
  METHODS
  WES was performed using genomic DNA from each case of EB, followed by massively parallel sequencing. Resulting reads were mapped to the human reference genome hg19. Sanger sequencing subsequently confirmed the potentially pathogenic mutations.
  
  
  RESULTS
  Overall, four unrelated families (6 patients) of JEB with a highly variable clinical presentation including a rare case of LOC syndrome were studied. WES revealed 4 variations in 3 genes (LAMA3, LAMB3 and COL17A1) that are implicated in JEB. None of the variations were recurrent. In addition we proposed the probable molecular consequence of a missense mutation on the structure-function relationship of lamininβ3 protein through computational modeling studies.
  
  
  CONCLUSIONS
  Being the first report documenting the phenotype-genotype correlations of JEB patients from India, our preliminary experience with WES is clearly encouraging and serves as a nidus for future large-scale molecular studies to actively identify and understand JEB patients in Indian population.
authors.affiliation: Departments of Dermatology & Venereology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Yenamandra
authors.affiliation: CSIR-Institute of Genomics & Integrative Biology, Mathura Road, New Delhi, India; Academy of Scientific and Innovative Research, CSIR, India.
authors.forename: Shamsudheen K
authors.initials: SK
authors.lastname: Vellarikkal
authors.affiliation: Departments of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Departments of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Madhumita R
authors.initials: MR
authors.lastname: Chowdhury
authors.affiliation: CSIR-Institute of Genomics & Integrative Biology, Mathura Road, New Delhi, India.
authors.forename: Rijith
authors.initials: R
authors.lastname: Jayarajan
authors.affiliation: CSIR-Institute of Genomics & Integrative Biology, Mathura Road, New Delhi, India.
authors.forename: Ankit
authors.initials: A
authors.lastname: Verma
authors.affiliation: CSIR-Institute of Genomics & Integrative Biology, Mathura Road, New Delhi, India; Academy of Scientific and Innovative Research, CSIR, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Scaria
authors.affiliation: CSIR-Institute of Genomics & Integrative Biology, Mathura Road, New Delhi, India; Academy of Scientific and Innovative Research, CSIR, India.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Sivasubbu
authors.affiliation: Departments of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Subrata B
authors.initials: SB
authors.lastname: Ray
authors.affiliation: Departments of Pathology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Dinda
authors.affiliation: Departments of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Madhulika
authors.initials: M
authors.lastname: Kabra
authors.affiliation: Departments of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Punit
authors.initials: P
authors.lastname: Kaur
authors.affiliation: Departments of Dermatology & Venereology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Sharma
authors.affiliation: Departments of Dermatology & Venereology, All India Institute of Medical Sciences, New Delhi, India. Electronic address: kgsethu@yahoo.com.
authors.forename: Gomathy
authors.initials: G
authors.lastname: Sethuraman
mesh_terms: D000293:Adolescent; D001324:Autoantigens / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D016109:Epidermolysis Bullosa, Junctional / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007194:India; D007223:Infant; D007797:Laminin / Q000235:genetics*; D008297:Male; D009154:Mutation; D024041:Non-Fibrillar Collagens / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA; D062606:Tertiary Care Centers; D000097794:Kalinin; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D015815:Cell Adhesion Molecules; D007797:Laminin; D024041:Non-Fibrillar Collagens; D000097794:Kalinin; D000097805:Collagen Type XVII; C095567:laminin alpha 3
keywords: Junctional epidermolysis bullosa; Protein modeling; Whole exome sequencing