Nance-Horan syndrome: linkage analysis in 4 families refines localization in Xp22.31-p22.13 region

Abstract

Nance-Horan syndrome (NHS) is an X-linked disease characterized by severe congenital cataract with microcornea, distinctive dental findings, evocative facial features and mental impairment in some cases. Previous linkage studies have placed the NHS gene in a large region from DXS143 (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 the Xp22.31-p22.13 region and linkage to the rest of the X chromosome can be excluded, our study shows that NHS is a genetically homogeneous condition. 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 yield a maximum Lod score of 9.45 with the support interval spanning a 15-cM region that includes DXS16 and DXS1229/365. The deletion map of the Xp22.3-Xp21.3 region suggests that the phenotypic variability of NHS is not related to gross rearrangement of sequences of varying size but rather to allelic 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 and PDHA1 genes in Xp22.2.

Mental retardation in Nance-Horan syndrome: Clinical and neuropsychological assessment in four families

“…Curiously, their unaffected brother had a profound mental impairment. A complete clinical and ophthalmological examination ruled out the possibility that MR in this subject may have been related to NHS, and the molecular analysis performed in this family [Toutain et al, 1997] clearly showed that he inherited a different haplotype from his affected brothers. Finally, the level of the single patient in family 4 showed that NHS may even be associated with high-normal intelligence.…”

“…No candidate gene has emerged either from the clinical pattern or from genetic data, although comparative mapping has allowed identification of a potential animal model in the mouse [Favor and Pretsch, 1990;Stambolian et al, 1994]. In a recent linkage study we refined the NHS gene localization in the Xp22.31-p22.13 region to a 15-18 cM interval between the loci DXS85 and DXS1226 [Toutain et al, 1997]. Genes for different specific and non-specific forms of XLMR have been mapped to the same region with overlapping localizations (Table IV).…”

“…The medical history and clinical picture concerning ophthalmological and dental problems will be described in detail elsewhere [Toutain et al, 1997]. Three of the families studied were typical NHS families with congenital cataract, evocative facial traits, typical dental anomalies, and mental impairment in patients of family 1.…”

“…The pathogenesis of NHS remains unknown. Linkage studies have placed the NHS gene in the Xp22.31-p22.13 region [Stambolian et al, 1990;Zhu et al, 1990;Bergen et al, 1994;Toutain et al, 1997]. Mild or moderate intellectual handicap was mentioned incidentally in seven NHS patients [Horan and Billson, 1974;Van Dorp and Delleman, 1979;Bixler et al, 1984;Lewis, 1989;Walpole et al, 1990].…”

Review Recent progress in identification and characterization of loci associated with sex-linked congenital cataract

“…However, it has certain limitations: the efficiency of small family analyses is very low, if it is carried out based on the LOD value. The loci in the Xp22.31-p22.13 region associated with Nance-Horan syndrome was refined by linkage analysis (Toutain et al, 1997).…”