RFLP discordance in a PKU family due to a deletion in the PAH gene.

We have previously reported preliminary data on a PKU family showing a discordant segregation of Pvu II (b) alleles at the PAH locus. A combination of several restriction enzymes and probe C2.6 (Intron 2) as well as STR typing were used to dissect the molecular structure of the PAH gene around exon 3. In this family, the results of this analysis and a re-examination of the physical map of the 5'-end of the gene provided strong evidence for the occurrence of a deletion removing exon 3. The "Sicilian" (approximately 2.5 kb) and "Yemenite Jew" (6.7 kb) deletions, the latter one also deleting exon 3, are different in terms of both the 5'-end breakpoint and apparent length. This study, besides adding a new member to the long and increasing list of nearly 200 PAH gene mutations, also proposes to undertake a careful evaluation of RFLP discordances incidentally detected at the PAH locus.

Definitive localization of X-linked Kallman syndrome (hypogonadotropic hypogonadism and anosmia) to Xp22.3: close linkage to the hypervariable repeat sequence CRI-S232.

Kallmann syndrome is a genetically heterogeneous disease characterized by hypogonadotropic hypogonadism and anosmia. Six families in which the disorder followed an X-linked inheritance were investigated by linkage analysis. Diagnostic criteria were uniformly applied and included tests for hypogonadotropic hypogonadism and anosmia. Close linkage was found by using the hypervariable repeated sequence CRI-S232 (DXS278) previously mapped to Xp22.3. At a maximum lod score of 6.5, the recombination fraction was calculated as .03. Of 30 fully informative meioses, one recombination between the disease locus and the loci recognized by probe CRI-S232 was observed. When an independent approach is used, these results confirm the X-linked Kallmann syndrome assignment previously made by deletion mapping, and allow definitive localization of the syndrome assignment previously made by deletion mapping, and allow definitive localization of the syndrome to the Xp22.3 region. This opens the way to carrier detection and to the identification of a gene responsible for this disorder.