Identification, by homozygosity mapping, of a novel locus for autosomal recessive congenital ichthyosis on chromosome 17p, and evidence for further genetic heterogeneity

Autosomal recessive congenital ichthyosis (ARCI) comprises a group of sever e disorders of keratinization, characterized by variable erythema and skin scaling. It is known for its high degree of genetic and clinical heterogene ity. Mutations in the gene for keratinocyte transglutaminase (TGM1) on chro mosome 14q11 were shown in patients with ARCI, and a second locus was descr ibed, on chromosome 2q, in families from northern Africa. Three other loci for ARCI, on chromosomes 3p and 19p, were identified recently. We have emba rked on a whole-genome scan for further loci for ARCI in four families from Germany, Turkey, and the United Arab Emirates. A novel ARCI locus was iden tified on chromosome 17p, between the markers at D17S938 and D17S1856, with a maximum LOD score of 3.38, at maximum recombination fraction 0.00, at D1 7S945, under heterogeneity. This locus is linked to the disease in the Turk ish family and in the German family. Extensive genealogical studies reveale d that the parents of the German patients with ARCI were eighth cousins. By homozygosity mapping, the localization of the gene could then be refined t o the 8.4-cM interval between D17S938 and D17S1879. It could be shown, howe ver, that ARCI in the two Arab families is linked neither to the new locus on chromosome 17p nor to one of the five loci known previously. Our finding s give evidence of further genetic heterogeneity that is not linked to dist inctive phenotypes.