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.