Isolated congenital nail dysplasia is an autosomal dominant disorder recently observed in a large family from southern Germany. The disorder is characterized by longitudinal streaks, thinning, and impaired formation of the nail plates leading to increased vulnerability of the free nail margins. In most cases, all fingernails and toenails are similarly involved with some accentuation of the thumb and great toenails. Histologic changes include hypergranulosis of the nail matrix and epithelial outgrowths from the nail bed. Patients do not show any alterations of hair growth and dentition, no malfunction of sweat glands and sensory organs, and no skeletal abnormalities. Isolated congenital nail dysplasia manifests from the first year of life with variable expressivity. In order to localize chromosomally the gene underlying isolated congenital nail dysplasia, linkage to the known keratin gene cluster regions on chromosomes 12q12 and 17q21 was ruled out first. The analysis of 150 microsatellite markers on various chromosomes mapped the isolated congenital nail dysplasia gene to the 6 cM interval between markers at D17S926 and D17S1528 on chromosome 17p13. Markers at D17S849, D17S1840, and D17S1529 co-segregated completely with the isolated congenital nail dysplasia locus. The maximum two-point LOD score was found for the marker at D17S1840 (Z(max) = 6.72 at Θ(max) = 0.00). The identified region harbors no currently known genes involved in skin or nail abnormalities. Isolated congenital nail dysplasia probably represents a novel isolated defect of nail development. The localization of this gene is, therefore, the first step towards the identification of a new factor in nail formation.