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X Linked Inheritance but Unlinked to the RP2 Or RP3 Loci

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X Linked Inheritance but Unlinked to the RP2 Or RP3 Loci 848 Med Genet 1994;31:848-852 Retinitis pigmentosa families showing apparent J Med Genet: first published as 10.1136/jmg.31.11.848 on 1 November 1994. Downloaded from X linked inheritance but unlinked to the RP2 or RP3 loci M A Aldred, P W Teague, M Jay, S Bundey, R M Redmond, B Jay, A C Bird, S S Bhattacharya, A F Wright Abstract linkage analysis and deletion patients.4"9-2 It is Three families with retinitis pigmentosa flanked distally by DXS84 and proximally by (RP) are described in which the disorder OTC and the proximal deletion breakpoint in shows apparent X linked inheritance but the patient BB." RP2 has been mapped by does not show linkage to the RP2 and RP3 linkage analysis alone and is flanked by the regions of the short arm of the X chro- markers DXS7 and DXS255.1"'4 mosome. The families are also in- In the course of analysing the linkage results consistent with a localisation ofthe disease in 40 XLRP families,'5 we identified three fam- gene between DXS164 and DXS28. In one ilies which fit neither an RP2 nor an RP3 case, reassessment of the family in the location. All three families were originally con- light of these results suggested that the sidered to have XLRP. We discuss whether family may have an autosomal dominant there might be other XLRP loci, or whether form of RP. The remaining two families these families might have autosomal dominant are consistent with X linkage and suggest RP (ADRP). the possibility of a new X linked RP (XLRP) locus. Materials and methods These families highlight the difficulties DNA extraction and analysis was carried out MRC Human Genetics in determining the mode ofinheritance on Unit, Western General as previously described.'617 The markers used Hospital, Crewe Road, the basis ofpedigree structure and clinical in this study are shown in table 1. Linkage Edinburgh EH4 2XU, data alone. Molecular genetics plays an analysis was carried out using the LINKAGE UK important role in confirming the mode M A Aldred v5.03 program package. Families were assumed P W Teague of inheritance and in detecting potential to show X linked segregation and multipoint A F Wright misclassifications, particularly in a group lod scores were calculated using LINKMAP. ofdisorders as heterogeneous as RP. They Department of Females were classified as obligate carriers if emphasise that caution is required in gen- Clinical they had an affected father or son, and other- http://jmg.bmj.com/ Ophthalmology, etic counselling of RP families, par- wise as of unknown genotype. Posterior prob- University of London, ticularly in the absence of any molecular Moorfields Eye abilities of linkage to RP2 or RP3 were Hospital, City Road, genetic analysis. calculated as described by Wright et al'6 and London EC1V 2PD, van Dorp et al.'5 Locations for the two loci UK (J7 Med Genet 1994;31:848-852) M Jay were assumed to be RP3 0G4 cM distal to OTC B Jay and RP2 6-5 cM proximal to DXS7.'5 A C Bird on September 25, 2021 by guest. Protected copyright. Retinitis is a group of retinal dis- Clinical Genetics Unit, pigmentosa FAMILY 23 Birmingham orders characterised by progressive retinal de- This family was ascertained through the Gen- Maternity Hospital, generation with pigmentary retinopathy, night Edgbaston, etic Eye Clinic in Birmingham and the pedigree Birmingham B15 2TG, blindness, and progressive reduction of the is shown in fig 1. Three of seven brothers have UK visual fields. It may be inherited as an auto- severe retinitis pigmentosa with onset in early S Bundey somal dominant, autosomal recessive, or X childhood. The now in linked recessive trait. Of X linked RP is mother, asymptomatic Departments of these, her eighties, was reported to show signs of Ophthalmology and one of the most severe forms, with affected being a carrier for X linked RP when examined Medical Genetics, The males commonly losing their central vision by Queen's University of the fourth or fifth decade of life. The family Belfast, Belfast City is very important in determining the Table 1 Polymorphic markers used in Hospital, Lisburn history DNA analysis Road, Belfast BT9 mode of inheritance, as the different forms 7AB, UK of RP are not sufficiently distinct to allow a Marker Location R M Redmond differential diagnosis to be made solely on clin- DXS85 Xp22.3-p22.2 of ical grounds.'2 DXS41 Xp22.1 Department DXS164 Xp21.1 Molecular Genetics, The X linked type of RP is itself genetically Institute of DXS206 Xp21.1 heterogeneous. There are at least two X linked DXS84 Xp21.1 Ophthalmology, 11-43 OTC Xp21.1 Bath Street, London genes, RP2 at Xpll.4-pll.2 and RP3 at DXS228 Xpll.4-pll.3 EC1V 9EL, UK Xp2l.1-pll.4.3 The existence of a third DXS7 Xpll.4-pll.3 SS Bhattacharya SYN/ARAF1 Xpll.23 XLRP gene, localised between DXS164 and TIMP Xpll.3-pll.23 Correspondence to DXS28, has been postulated.45 However, OATL1 Xpll.3-pll.23 Dr Wright. DXS255 Xpl1.22 patients deleted for this region of Xp have DXS146 Xpl1.22 Received 1 July 1993 not been shown to have RP.8 The region DXS1 Xqll.2-ql2 Revised version accepted for DXYS1X Xq21.31 publication 20 June 1994 containing the RP3 gene has been defined by Retinitis pigmentosa families showing apparent X linked inheritance but unlinked to the RP2 or RP3 loci 849 1 51 Hospital, London. The pedigree structure is I more immediately suggestive of X linked in- heritance than F23, although again there are J Med Genet: first published as 10.1136/jmg.31.11.848 on 1 November 1994. Downloaded from 2 1 no affected males documented in the early 1 2 generations. Subject III.3 was first diagnosed 2 1 as having RP at the age of 24 and is now 1 2 registered as partially sighted. Subject II.2 has suffered an 2 1 night blindness from early age. II. 1 has refused to be examined. 1 2 1 2 1 2 FAMILY 56 1 2 This family, also ascertained through the Gen- 1 2 etic Clinic at Moorfields Eye Hospital, has 1I 2 been previously reported by Redmond et al. 9 It contains a large sibship with five males severely affected with RP (fig 3). They all developed ~b3 5 6 7 II , E2 night blindness before the age of 10, have _ _ Markers extinguished ERGs, poor visual acuities, pos- terior subcapsular lens opacities, and advanced 1 2 1 2 2 DXS85 fundus changes. These clinical details are 2 1 2 2 2 1 DXS41 shown in table 2. Their mother has peripheral 1 1 1 2 DXS 164 bone spicule retinopathy and subnormal ERG 1 1 1 2 2 2 1 DXS206 with good vision at the age of 68, suggesting 2 2 2 1 1 1 2 DXS84 that she is a carrier of XLRP. Three of her 1 1 1 1 1 2 1 DXS228 daughters have scattered pigmentation of the 1 1 1 1 1 2 1 SYN/ARAF retina or thinning of the retinal pigment epi- 1 1 1 1 1 2 1 TIMP thelium or both, but normal vision, normal 2 1 1 1 1 2 1 DXS255 electrophysiology, and no night blindness, in- are 2 1 1 1 1 2 1 DXS1 dicating that they carriers ofXLRP. A male in the third generation who is the son of a 2 1 2 2 1 2 1 DXYS1X potential carrier female has recently been re- ported to show pigmentation of the fundus at 10 years of age. The boy is asymptomatic at present. It is hoped that psychophysical tests can be performed to establish whether or not * male Affected he is affected by RP. There is no family history of RP in previous generations. 0 Deceased unaffected male http://jmg.bmj.com/ Results Female assumed to be an obligate carrier (9) HAPLOTYPE ANALYSIS The pedigrees and segregation ofmarker alleles C Female showing carrier phenotype are shown in figs 1 to 3. The haplotypes shown are those which minimise the total number of ( ) Inferred recombinants. on September 25, 2021 by guest. Protected copyright. Figure 1 Segregation of marker alleles in F23. The affected haplotpe is shown as a FAMILY 23 thick solid line and recombinants as a change in shading. Before examination of Eleven markers were informative (fig 1), cov- markers between DXS84 and DXS255, this family was thought to be RP2 type, as RP ering most of Xp and extending to proximal apparently segregated with allele 2 at DXS255 with only one recombinant (II. 7). However, additional markers and haplotype analysis showed that subjects II. 6 and II. 7 Xq. At all of these loci except DXS85, subjects have different alleles at all marker loci except for DXS85. Thus it is unlikely that RP2 II.6 and 11.7, who are both affected, have or RP3 could be the disease locus. different alleles. On the basis of these results, together with those from the rest ofthe sibship, 30 years ago. The father died at age 60 having it is unlikely that the disease locus resides within had a normal fundus examination. There is no the region covered by these markers, unless known earlier history of RP in this family. The more complicated haplotypes with double re- daughters of affected male 11.6 show patches combinants are invoked. of pigmentation in the periphery of their fundi, characteristic of the carrier state, and the single daughter of 11.7 shows patchy peripheral pig- FAMILY 54 mentation and a slightly reduced scotopic re- Nine loci were informative in one or both of sponse on electroretinography (ERG).
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