93 – 95 Initial attempts to identify this X-linked susceptibility locus by standard linkage analysis were unsuccessful, 96 – 99 but two recent studies using a larger number of more extensively defined LHON pedigrees found two overlapping disease loci with highly significant LOD scores at Xp21–Xq21 100 and Xq25–27.2. 101 Although the actual causative gene in this region of interest has not yet been identified, a high risk haplotype [DXS8090(166)-DXS1068(268)] at Xp21 was defined which increased the risk of visual failure ∼35-fold for the m.11778G>A and m14484T>C mutations but not for m.3460G>A. 100 The possibility of other autosomal nuclear modifier genes in LHON has not been excluded and the genetic aetiology of LHON might prove even more complex, with epistatic interaction of these multiple nuclear susceptibility loci and genetic heterogeneity.
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