Mutational spectrum in 101 patients with hypohidrotic ectodermal dysplasia and breakpoint mapping in independent cases of rare genomic rearrangements.

Hypohidrotic ectodermal dysplasia (HED), a rare and heterogeneous hereditary disorder, is characterized by deficient development of multiple ectodermal structures including hair, sweat glands and teeth. If caused by mutations in the genes EDA, EDA1R or EDARADD, phenotypes are often very similar as the result of a common signaling pathway. Single-nucleotide polymorphisms (SNPs) affecting any gene product in this pathway may cause inter- and intrafamilial variability. In a cohort of 124 HED patients, genotyping was attempted by Sanger sequencing of EDA, EDA1R, EDARADD, TRAF6 and EDA2R and by multiplex ligation-dependent probe amplification (MLPA). Pathogenic mutations were detected in 101 subjects with HED, affecting EDA, EDA1R and EDARADD in 88%, 9% and 3% of the cases, respectively, and including 23 novel mutations. MLPA revealed exon copy-number variations in five unrelated HED families (two deletions and three duplications). In four of them, the genomic breakpoints could be localized. The EDA1R variant rs3827760 (p.Val370Ala), known to lessen HED-related symptoms, was found only in a single individual of Asian origin, but in none of the 123 European patients. Another SNP, rs1385699 (p.Arg57Lys) in EDA2R, however, appeared to have some impact on the hair phenotype of European subjects with EDA mutations.