Mizrachi-Koren Mordechai, Shemer Saar, Morgan Michal, Indelman Margarita, Khamaysi Ziad, Petronius Danny, Bitterman-Deutsch Ora, Hennies Hans Christian, Bergman Reuven, Sprecher Eli
Laboratory of Molecular Dermatology and Department of Dermatology, Rambam Medical Center, Haifa, Israel.
J Am Acad Dermatol. 2006 Sep;55(3):393-401. doi: 10.1016/j.jaad.2006.02.020. Epub 2006 Jun 16.
The routine diagnosis of genodermatoses is significantly complicated by the fact that in this group of disorders, clinical manifestations may result from mutations in unrelated genes (genetic heterogeneity) and mutations in the same gene often lead to dissimilar clinical signs (phenotypic heterogeneity).
In this study, we applied the principles of homozygosity mapping as a screening method before formal mutational analysis in an attempt to facilitate the molecular diagnosis of genodermatoses in consanguineous families. The method was evaluated in a retrospective fashion in 4 families previously assessed with junctional epidermolysis bullosa and in a prospective manner in 11 families with congenital recessive ichthyosis.
The method was found to be efficient in directing the molecular analysis to one of the 4 genes commonly involved in the pathogenesis of junctional epidermolysis bullosa or in identifying cases of congenital recessive ichthyosis caused by mutations in TGM1. We found that this diagnostic strategy results in a 5-fold decrease in the cost of mutation analysis.
The proposed diagnostic strategy is applicable to consanguineous families only and, therefore, cannot be used in outbred populations.
Our results indicate that homozygosity mapping may serve as a useful adjunct in the molecular diagnosis of junctional epidermolysis bullosa or congenital recessive ichthyosis in inbred populations. This study emphasizes the usefulness in human genetics of diagnostic strategies tailored to the demographic features of target populations.
遗传性皮肤病的常规诊断存在显著困难，因为在这组疾病中，临床表现可能由不相关基因的突变（遗传异质性）引起，而同一基因的突变往往导致不同的临床体征（表型异质性）。
在本研究中，我们在进行正式的突变分析之前，应用纯合性定位原则作为一种筛选方法，试图促进近亲家庭中遗传性皮肤病的分子诊断。该方法在4个先前已评估交界性大疱性表皮松解症的家庭中进行了回顾性评估，并在11个先天性隐性鱼鳞病家庭中进行了前瞻性评估。
发现该方法在将分子分析导向交界性大疱性表皮松解症发病机制中通常涉及的4个基因之一或识别由TGM1突变引起的先天性隐性鱼鳞病病例方面是有效的。我们发现这种诊断策略使突变分析成本降低了5倍。
所提出的诊断策略仅适用于近亲家庭，因此不能用于非近亲人群。
我们的结果表明，纯合性定位可能是近亲人群中交界性大疱性表皮松解症或先天性隐性鱼鳞病分子诊断的有用辅助手段。本研究强调了根据目标人群的人口统计学特征量身定制的诊断策略在人类遗传学中的有用性。
