Yenamandra Vamsi K, Vellarikkal Shamsudheen K, Kumar Manoj, Chowdhury Madhumita R, Jayarajan Rijith, Verma Ankit, Scaria Vinod, Sivasubbu Sridhar, Ray Subrata B, Dinda Amit K, Kabra Madhulika, Kaur Punit, Sharma Vinod K, Sethuraman Gomathy
Departments of Dermatology & Venereology, All India Institute of Medical Sciences, New Delhi, India.
CSIR-Institute of Genomics & Integrative Biology, Mathura Road, New Delhi, India; Academy of Scientific and Innovative Research, CSIR, India.
J Dermatol Sci. 2017 Apr;86(1):30-36. doi: 10.1016/j.jdermsci.2016.12.020. Epub 2016 Dec 29.
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.
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.
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.
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.
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.
交界性大疱性表皮松解症（JEB）是一组与皮肤极度脆弱相关的遗传性皮肤病。尽管有几项特征明确的遗传学研究，但对这一异质性群体进行分子诊断仍具有挑战性。基因组学领域的最新进展表明，全外显子组测序（WES）已成功应用于多种遗传性皮肤病的快速高效诊断策略。
鉴于印度对JEB分子研究的稀缺性和需求，我们试图探索WES在了解这种罕见的、某些亚型具有致死性的EB亚组突变谱方面的潜力。
使用来自每个EB病例的基因组DNA进行WES，随后进行大规模平行测序。所得读数与人类参考基因组hg19进行比对。随后通过桑格测序确认潜在的致病突变。
总体而言，研究了4个无关的JEB家族（6名患者），其临床表现高度可变，包括1例罕见的LOC综合征病例。WES揭示了与JEB相关的3个基因（LAMA3、LAMB3和COL17A1）中的4个变异。这些变异均非复发性。此外，我们通过计算建模研究提出了一个错义突变对层粘连蛋白β3蛋白结构-功能关系的可能分子后果。
作为第一份记录印度JEB患者表型-基因型相关性的报告，我们使用WES的初步经验显然令人鼓舞，并为未来大规模分子研究提供了一个契机，以便积极识别和了解印度人群中的JEB患者。
