Centre for Human Genetics, Electronic city Phase - I, Bangalore, Karnataka, India.
Department of Pediatrics and Dermatology, Manipal Hospital, Bangalore, Karnataka, India.
PLoS One. 2023 Aug 9;18(8):e0289558. doi: 10.1371/journal.pone.0289558. eCollection 2023.
Dystrophic epidermolysis bullosa (DEB) is due to variation in the COL7A1 gene. The clinical phenotype and severity depends on the type of variation and domain of the affected protein.
To characterize the spectrum of COL7A1 variations in a cohort of DEB patients from India, to correlate these findings with clinical phenotypes and to establish a genotype-phenotype correlation.
This was a retrospective, observational study involving patients with DEB diagnosed on the basis of clinical manifestations, Immuno-fluorescence antigen mapping (IFM) and genetic analysis. A genotype-phenotype correlation was attempted and observations were further explained using IFM on skin biopsies and molecular dynamic simulations. Descriptive statistics were performed using SPSS version 20.0 with P values of <0.05 considered significant.
We report 68 unrelated Indian DEB patients classified as RDEB-Intermediate (RDEB-I), RDEB-Severe (RDEB-S) or DDEB based on the EB diagnostic matrix, immunofluorescence antigen mapping and genetic data. Of 68 DEB patients, 59 (86.76%) were inherited in a recessive pattern (RDEB) and 9 (13.24%) in a dominant pattern (DDEB). Limbal stem cell deficiency was seen in four cases of RDEB-S very early in the course of the disease. A total of 88 variants were detected of which 66 were novel. There were no hotspots and recurrent variations were seen in a very small group of patients. We found a high frequency of compound heterozygotes (CH) in RDEB patients born out of non-consanguineous marriage. RDEB patients older than two years who had oral mucosal involvement, and/or deformities, were more likely to have esophageal involvement. Genotype phenotype correlation showed a higher frequency of extracutaneous manifestations and deformities in patients with Premature Termination Codons (PTCs) than in patients with other variations. Molecular simulation studies in patients with missense mutations showed severe phenotype when they were localized in interrupted regions of GLY-X-Y repeats.
This large study of DEB patients in South Asia adds to the continually expanding genetic database of this condition. This study has direct implications on management as this group of patients can be screened early and managed appropriately.
营养不良型大疱性表皮松解症（DEB）是由于 COL7A1 基因的变异引起的。临床表型和严重程度取决于变异类型和受影响蛋白的结构域。
描述来自印度 DEB 患者队列中 COL7A1 变异的谱，将这些发现与临床表型相关联，并建立基因型-表型相关性。
这是一项回顾性观察性研究，涉及根据临床表现、免疫荧光抗原定位（IFM）和基因分析诊断为 DEB 的患者。尝试进行基因型-表型相关性，并进一步通过皮肤活检的 IFM 和分子动力学模拟进行观察。使用 SPSS 版本 20.0 进行描述性统计，P 值<0.05 被认为具有统计学意义。
我们报告了 68 例无亲缘关系的印度 DEB 患者，根据 EB 诊断矩阵、免疫荧光抗原定位和遗传数据，将其分为 RDEB-中间型（RDEB-I）、RDEB-严重型（RDEB-S）或 DDEB。在 68 例 DEB 患者中，59 例（86.76%）为隐性遗传（RDEB），9 例（13.24%）为显性遗传（DDEB）。在疾病早期，4 例 RDEB-S 患者出现了角膜缘干细胞缺乏。共检测到 88 种变异，其中 66 种为新变异。没有热点和反复出现的变异，而且只在一小部分患者中出现。我们发现，非近亲结婚的 RDEB 患者中存在高频的复合杂合子（CH）。2 岁以上有口腔黏膜受累和/或畸形的 RDEB 患者更有可能出现食管受累。基因型-表型相关性显示，提前终止密码子（PTC）患者比其他变异患者更易出现皮肤外表现和畸形。对错义突变患者的分子模拟研究表明，当突变发生在 GLY-X-Y 重复的中断区域时，表型更为严重。
这项对南亚 DEB 患者的大型研究增加了该疾病不断扩大的基因数据库。这项研究对管理有直接影响，因为可以对这组患者进行早期筛查并进行适当的管理。
