NANCE-HORAN SYNDROME - LINKAGE ANALYSIS IN 4 FAMILIES REFINES LOCALIZATION IN XP22.31-P22.13

Nance-Horan syndrome (NHS) is an X-linked disease characterized by sev ere congenital cataract with microcornea, distinctive dental findings, evocative facial features and mental impairment in some cases. Previo us linkage studies have placed the NHS gene in a large region from DXS 143 (Xp22.31) to DXS451 (Xp22.13). To refine this localization further , we have performed linkage analysis in four families. As the maximum expected Lod score is reached in each family for several markers in th e Xp22.31-p22.13 region and linkage to the rest of the X chromosome ca n be excluded, our study shows that NHS is a genetically homogeneous c ondition. An overall maximum two-point Lod score of 9.36 (theta=0.00) is obtained with two closely linked markers taken together, DXS207 and DXS1053 in Xp22.2. Recombinant haplotypes indicate that the NHS gene lies between DXS85 and DXS1226. Multipoint analysis yields a maximum L od score of 4.45 with the support interval spanning a 15-cM region tha t includes DXS16 and DXS1229/365. The deletion map of the Xp22.3-Xp21. 3 region suggests that the phenotypic variability of NHS is not relate d to gross rearrangement of sequences of varying size but rather to al lelic mutations in a single gene, presumably located proximal to DXS16 and distal to DXS1226. Comparison with the map position of the mouse Xcat mutation supports the location of the NHS gene between the GRPR a nd PDHA1 genes in Xp22.2.