Dilemmas in distinguishing between dominant and recessive forms of dystrophic epidermolysis bullosa

Summary Background Dystrophic epidermolysis bullosa (DEB) is a heterogeneous inherited blistering skin disorder. The mode of inheritance may be autosomal dominant or recessive but all forms of DEB result from mutations in the gene encoding the anchoring fibril protein, type VII collagen, COL7A1. Consequently, in spite of careful clinical and skin biopsy examination, it may be difficult to distinguish mild recessive cases from de novo dominant disease in families with clinically normal parents and no other affected siblings; this distinction has significant implications for the accuracy of genetic counselling. Objectives To assess whether COL7A1 mutation analysis might help determine mode of inheritance in mild to moderate DEB. Methods We performed COL7A1 screening using heteroduplex analysis and direct nucleotide sequencing in four individuals with mild to moderate ‘sporadic’ DEB and clinically unaffected parents. Results In each patient, we identified a heterozygous glycine substitution within the type VII collagen triple helix. However, in two cases these mutations had been inherited in trans with a non‐sense mutation on the other allele (i.e. autosomal recessive DEB). In the other two cases, no additional mutation was identified and neither mutation was present in parental DNA (i.e. de novo dominant disease). Conclusions This study highlights the usefulness of DNA sequencing in determining the inherited basis of some sporadic cases of DEB. However, delineation of glycine substitutions should prompt comprehensive COL7A1 gene sequencing in the affected individual, as well as clinical assessment of parents and mutation screening in parental DNA, if the true mode of inheritance is to be established correctly.