SCARCITY OF MUTATIONS DETECTED IN FAMILIES WITH X-LINKED HYPOHIDROTICECTODERMAL DYSPLASIA - DIAGNOSTIC IMPLICATIONS

Indirect molecular diagnosis of X linked hypohidrotic ectodermal dyspl asia (XLHED), a congenital disorder of hair, teeth, and eccrine sweat glands, has been possible by linkage analysis. Direct mutation detecti on would enable carrier detection in female relatives of sporadic case s, as well as help distinguish XLHED from the rarer, clinically indist inguishable, autosomal recessive disorder ARHED. Recently, a candidate gene for XLHED has been identified. Genomic DNA from 162 affected mal es and 21 females, who were either obligate carriers or had manifestat ions of the disorder, were screened by SSCP analysis. A subset of the patients had been previously screened for large genomic deletions and had limited screening of a single exon by SSCP analysis. The two known exons were amplified using flanking primers. Approximately 7% of pati ents, all males, had putative mutations identified within exon 1, but no variants were found within exon 2. Ten different putative mutations and four probable polymorphisms were identified. Both of the known ex ons were sequenced in 10 patients who had no detectable SSCP changes, but no additional mutations were found. No correlation between phenoty pe and genotype was evident between either affected subjects or subjec ts with or without detectable mutations. The results of the study indi cate that only a small minority of affected males can be diagnosed by direct mutation analysis, and that the remainder of the patients are l ikely to have mutations in as yet unidentified exons of the EDA gene. Linkage analysis, in informative situations, therefore remains the onl y practical diagnostic option available.