Homozygosity mapping as a screening tool for the molecular diagnosis of hereditary skin diseases in consanguineous populations.

[junctional epidermolysis bullosa]

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 TGM 1 . 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 , can not 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 .

Diseases
Validation

Diseases presenting "dissimilar clinical signs" symptom

junctional epidermolysis bullosa

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