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Multilocus linkage analysis of 62 family pedigrees with X chromosome-linked retinitis pigmentosa (XLRP) was undertaken to determine the presence of possible multiple disease loci and to reliably estimate their map location. Multilocus homogeneity tests furnished convincing evidence for the presence of two XLRP loci, the likelihood ratio being 6.4 x 109:1 in favor of two versus a single XLRP locus and gave accurate estimates for their map location. In 60-75% of the families, location of an XLRP gene was estimated at 1 centimorgan distal to OTC, and in 25-40% ofthe families, an XLRP locus was located halfway between DXS14 (p58-1) and DXZJ (Xcen), with an estimated recombination fraction of 25% between the two XLRP loci. There is also good evidence for a third XLRP locus, midway between DXS28 (C7) and DXS164 (pERT87), supported by a likelihood ratio of 293:1 for three versus two XLRP loci.Retinitis pigmentosa (RP) is a group of hereditary progressive disorders of the retina characterized initially by night blindness, often within the first two decades of life, reduction of peripheral or side vision, eventual decrease in central vision to variable degrees, in many cases leading to total blindness due to degeneration of the retina (1). There are several subtypes of RP, including autosomal recessive, autosomal dominant, and X chromosome-linked forms (XLRP).Linkage analyses in families with XLRP have shown conflicting results regarding the location of the disease locus. Consequently, the presence of two XLRP loci was hypothesized (2-5). One subtype of XLRP, referred to as RP2, was linked to locus DXS7 (L1.28) (6, 7); another subtype, RP3, was linked to locus OTC (ornithine carbamoyltransferase) (8-10). Further evidence for location of an XLRP locus distal to OTC came from a patient with a deletion starting between OTC and DXS84 (754) and extending toward the telomere, in whom several X-chromosome linked diseases occurred including RP (11). Friedrich et al. (12) found another locus responsible for XLRP to be closely linked to DXS7, between Xcen and DXS7 (L1.28).The current study was initiated as a collaborative effort (i) to obtain evidence for XLRP heterogeneity if at all present, and, if so, (ii) to localize the disease loci in a comprehensive linkage and heterogeneity analysis.Family Data. A total of 62 families were available for this analysis, most but not all of which have been published previously. For calculation efficiency, some pedigrees had earlier been broken down into smaller families and analyzed separately; here, they were analyzed undivided. Disease status for both affected males and carrier females was determined by the investigators and was incorporated unaltered in this analysis.In many cases, heterozygous women also have symptoms that are, however, generally much milder than in men. Where detectable, such symptoms have been used for carrier status determination.Linkage Analysis. The linkage analysis was carried out with the LINKAGE programs version 4.7 (13). Map distances between markers whos...

The intragenic heterogeneity encountered in many dominant disease-causing genes represents a significant challenge with respect to development of economically viable therapeutics. For example, 25% of autosomal dominant retinitis pigmentosa is caused by over 100 different mutations within the gene encoding rhodopsin, each of which could require a unique gene therapy. We describe here an RNA interference (RNAi)-based mutation-independent approach, targeting as an example murine rhodopsin. Native transcripts are suppressed by a single RNAi molecular species, whereas transcripts from replacement genes engineered at degenerate third-codon wobble positions are resistant to suppression. We demonstrate suppression of murine rhodopsin transcript by up to 90% with full concomitant expression of replacement transcript and establish the validity of this approach in cell culture, retinal explants, and mouse liver in vivo.

IMPORTANCEThe mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management.OBJECTIVE To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1.DESIGN, SETTING, AND PARTICIPANTS Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020.MAIN OUTCOMES AND MEASURES Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed.RESULTS A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P = .02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P = .005).CONCLUSIONS AND RELEVANCE This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1.

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