British ournal of Ophthalmology 1995; 79: 841-846

Bimodal expressivity in dominant retinitispigmentosa genetically linked to chromosome 19q

K Evans, M Al-Maghtheh, F W Fitzke, A T Moore, M Jay, C F Inglehearn, G B Arden,A C Bird

AbstractA clinical, psychophysical, and electro-physiologic study was undertaken of twoautosomal dominant retinitis pigmentosapedigrees with a genetic mutation assignedto chromosome 19q by linkage analysis.Members with the abnormal haplotypewere either symptomatic with adolescentonset nyctalopia, restricted visual fields,and non-detectable electroretinographicresponses by 30 years of age, or asympto-matic with normal fundus appearance andminimal or no psychophysical or electro-retinographic abnormalities. There wasno correlation in the severity in parentsand their offspring. Pedigree analysissuggested that although the offspring ofparents with the genetic mutation were at50%/o risk of having the genetic defect, therisk of being symptomatic during a work-ing lifetime was only 31%. Such bimodalphenotypic expressivity in these particularpedigrees may be explained by a second,allelic genetic influence and may be aphenomenon unique to this genetic locus.Genetic counselling in families expressingthis phenotype can only be based on haplo-type analysis since clinical investigations,even in the most elderly, would not pre-clude the presence ofthe mutant gene.(BrJ7 Ophthalmol 1995; 79: 841-846)

Department of ClinicalOphthalmology andElectrodiagnostics,Moorfields EyeHospitalK EvansM JayG B ArdenA T MooreA C Bird

Departments ofVisualSciences andMolecular Genetics,Institute ofOphthalmology,LondonFW FitzkeC F IngleheamM Al-Maghtheh

Correspondence to:K Evans, Department ofClinical Ophthalmology,Moorfields Eye Hospital,City Road, LondonEC1V 2PD.

Accepted for publication24 April 1995

Epidemiological studies of retinitis pigmentosaconsistently report a frequency of one in 5000of the general population suggesting that thereare approximately 100 000 retinitis pigmentosasufferers in Europe and a similar number in theUSA.' A family history of retinitis pigmentosacan be demonstrated in approximately 50% ofnew cases, and all three mendelian inheritancepatterns occur. Autosomal dominant inheri-tance accounts for approximately 17-25% ofall casesl-3 and the condition has been foundto be genetically heterogeneous. Over 60 dif-ferent mutations in the rhodopsin gene onchromosome 3q4 and 18 peripherin/RDSgene mutations5 have been found in differentautosomal dominant retinitis pigmentosapedigrees. Five other loci for dominant retinitispigmentosa genes have been identified onchromosomes 7p,6 7q,7 8cen,8 17p,9 and 19ql'by genetic linkage analysis.

In addition to the genetic diversity seen inautosomal dominant retinitis pigmentosa,phenotypic variability is also well established.Differences in clinical presentation have beenreported between different families. Differencesbetween members of the same family, variable

expressivity, is also a common characteristic ofautosomal dominant disease." Here we reportan extended clinical, psychophysical, andelectrophysiological study of two familiesexpressing a retinitis pigmentosa phenotypegenetically linked to chromosome 19q.10Haplotype data have now allowed sound geneticdiagnosis, making it possible to compare accur-ately the severity of disease in patients with thatin their offspring. This has led to the identifica-tion of a large number of asymptomatic individ-uals carrying the disease gene suggesting anunusual polarity ofphenotype in that those withthe disease gene seem either to be severelyafflicted or are asymptomatic with little psycho-physical or electroretinographic abnormality, aphenotype unlike that reported in other retinitispigmentosa genotypes.

Patients and methodsSome clinical details on these unrelatedfamilies have been reported previously (family3 and 4 respectively).'2 The former originatesin south Wales and the latter from northeastEngland. Further clinical studies and linkageanalysis have allowed the identification of eightsymptomatic and eight disease haplotypecarriers not included in the previous report.Autosomal dominant inheritance is evidentwith symptomatic individuals in each genera-tion and male to male transmission.Asymptomatic patients were assigned as hav-ing the causative genetic mutation if they hadthe same haplotype as symptomatic individualswithin a 20 centimorgan region of chromo-some 19q. Family members with this haplo-type have a >98% probability of carrying thedisease mutation.'0 Thirty individuals wereidentified as having the abnormal gene andenrolled into the study. In family '3' thisincluded five symptomatic individuals and fourasymptomatic individuals with the diseasehaplotype. One of these asymptomaticpatients, an obligate carrier, had a sympto-matic child. In family '4', 13 symptomaticpatients and eight asymptomatic individualswith the disease haplotype were examined(including three obligate carriers).An extensive ophthalmic history was

recorded including details of visual acuity lossand age of onset of nyctalopia. Full oph-thalmic examination was undertaken whichincluded assessment of visual acuity, exami-nation of the anterior segment and fundus.To assess whether or not a systemic abnor-mality might segregate with ocular disease, adetailed general medical history and a briefphysical examination were undertaken.

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A

11

III

IV

V

VI

B

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11

III

IV

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V m0C0 006 b 0 XFigure 1 Pedigrees forfamilies 3 (A) and 4 (B). * Symptomatic male, 0 unaffectedfemale, (Odisease-haplotype carrier.Bar above symbol identifies patients who underwent DNA examination.

For psychophysical studies pupils weredilated with 1% cyclopentolate hydrochlorideand 2-5% phenylephrine hydrochloride, andsubjects dark adapted for 40 minutes. Darkadapted static perimetry was undertaken usinga modified Humphrey automated perimeter(Allergan Humphrey, San Leandro, CA,USA).'3'5 Cone and rod sensitivities wereassessed using a standard Humphrey 30-2 pro-gram with the background illumination turnedoff. Size 5 red and blue test stimuli were used.In each case the eye with the better visualacuity was tested. For dark adaptometry, pre-bleach thresholds were then determined atselected positions. Patients were exposed tobright white light for 2 minutes sufficient tobleach 95% of rhodopsin (7.5 log scotopicTr6land-second delivered over 45 seconds).Recovery of sensitivity with time was assessedwith size 5 blue test stimuli.'6'8

Selected subjects underwent electrophysio-logical investigation using a 'short-protocol'adapted from that recommended by theInternational Standard for Clinical Oph-thalmology.'920 Dark adapted electroretino-graphy including blue flash ('run 7' to elicit rodisolated responses), red flash ('run 18', conedominated responses), white flash ('run 20',mixed photoreceptor responses) and 30 Hzflicker ('run 31' cone isolated) responses wererecorded. Electro-oculography was performedas previously described.21

The study was approved by the local ethicscommittee and informed consent was obtainedfrom each subject enrolled into the study.

ResultsRevised pedigrees are presented in Figures 1Aand 1B. Linkage studies in both families iden-tified seven individuals as recombinant overthe entire 19q linked region. This prompted areappraisal of their clinical status which hadpreviously been based on ophthalmic historyonly. These examinations resulted in redesig-nation of disease status of two subjects inpedigree 3 (3-III-14 and 3-IV-20 as pheno-typically normal) and five in pedigree 4(4-III-7, 4-IV-1, and 4-IV-15 as phenotypi-cally abnormal, 4-IV-25 and 4-IV-46 asnormal). This and the identification of nineextra asymptomatic disease haplotype carriersaccounts for differences from previously pub-lished family trees, more accurately reflectingsegregation of the disease.'2 Because informa-tion was based on historical data in somegenerations, segregation of disease status wasexamined in generations III-V only in pedi-gree 3 and II-IV only in pedigree 4. Thisidentified 57 symptomatic plus disease haplo-type carriers and 63 unaffected individualsborn to symptomatic or disease haplotypecarrier parents. Approximately half (48%) ofat risk individuals had inherited the disease

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Table 1 Clinical details of30 symptomatic and disease haplotype camrier patients

Nyctalopia Visual acuityAge Genetic age at onset Lens

Patient (years) status (years) Right Left opacities Fundal examination

3-IV-2 62 s 6 6/60 6/60 PSC MA, PEA, BS 360°3-IV-15 61 s 10 6/36 6/36 PSC MA, PEA, BS 360°3-V-2 24 s 11 6/9 6/9 None PEA, BS, BS 360°3-V-5 57 s 15 6/9 6/12 PSC PEA, BS 360'3-V-6 52 s 9 6/24 6/36 None PEA, BS 360'4-III-I 61 s 8 6/60 6/60 PSC, CO PEA, BS 360'4-III-2 50 s 9 6/18 6/12 PSC PEA, BS 360'4-III-3 54 s 18 6/18 6/9 PSC MO, PEA, BS 360'4-III-13 60 s 10 6/60 6/60 PSC MO, PEA, BS 360'4-III-15 52 s 5 6/9 6/9 PSC PEA, BS 360'4-III-29 48 s 4 <3/60 <3/60 PSC MA, PEA, BS 360'4-IV-1 26 s No <3/60* 6/6 None ONH, PEA, BS 360'4-IV-8 25 s 5 6/12 6/12 PSC MO, BS 360'4-IV-1 45 s 5 6/18 6/9 PSC PEA, BS 360'4-IV-29 25 s 8 6/6 6/6 None PEA, BS 360'4-IV-38 33 s 13 6/12 6/9 None MO, PEA, BS 360'4-IV-39 30 s 10 6/9 6/9 None PEA, BS 360'4-IV-43 28 s 15 6/9 6/5 None MO, BS 360'3-IV-5 57 d No 6/6 6/9 None Nornal3-IV-6 55 d No 6/6 6/6 None Nornal3-V-13 33 d No 6/6 6/6 None Nornal3-V-16 24 d No 6/5 6/5 None Normal4-III-5 75 d No 6/9 6/9 CO Normal4-III-25 49 d No 6/5 6/6 None Normal4-III-27 57 d No 6/6 6/6 None Normal4-III-28 55 d No 6/9 6/9 CO Normal4-IV-6 28 d No 6/6 6/6 None Normal4-IV-9 26 d No 6/9 6/6 None Normal4-IV-20 30 d No 6/6 6/6 None Normal4-IV-40 26 d No 6/6 6/6. None Normal

3=Pedigree fig 1A, 4=pedigree Fig lB. s=Symptomatic, d=disease haplotype carrier.PSC=posterior subcapsular lens opacities, CO=cortical lens opacities, PEA=retinal pigmentepithelial atrophy, BS=bone spicule retinal pigmentation, MO=macular oedema, MA=macularatrophy, *=reduced acuity owing to optic nerve head hypoplasia (ONH) urelated to retinitispigmentosa.

haplotype but only 37 (31%) were sympto-matic.

Seventeen symptomatic patients had eight(47%) symptomatic and nine (53%) diseasehaplotype carrier children. This comparedwith 12 asymptomatic disease haplotypecarrier patients who had 19 (76%) sympto-matic and six (24%) disease haplotype carrierchildren. The difference between the percent-ages of symptomatic children born to sympto-matic and asymptomatic disease haplotypecarrier parents was not statistically significant(x2=3 7, p=0 05). Of the 27 symptomaticindividuals whose parents were also includedin generations III-V of pedigree 3 and II-IV ofpedigree 4, 17 had a male parent carrying thedisease gene and 10 a female parent. Of 15asymptomatic disease haplotype carriers withparents included in these generations 10 had a

Table 2 Dark adapted static sensitivities. Loss relative to lower normal limit

Dark adapted sensitivity loss (dB)

Blue stimulus Red stimulusGenetic

Patient status 3' 9' 27' 3' 9' 27'3-IV-15 s 28 31 31 22 26 263-V-2 s 6 31 31 7 26 263-V-5 s 27 31 31 15 26 263-V-6 s 28 31 31 26 26 264-III-15 s 31 31 31 16 26 264-IV-lI s 15 31 31 4 22 264-IV-29 s 4 10 31 6 22 264-IV-38 s 23 31 31 13 26 263-IV-5 d 2 1 0 0 0 03-NV-6 d 0 0 0 0 0 03-V-113 d 0 0 0 0 0 03-V-116 d 0 0 0 0 0 04-III-5 d 2 1 2 0 0 04-HI1-25 d 2 1 1 0 0 04-III-27 d 6 5 2 2 04-III-28 d 0 0 0 0 0 04-NV-40 d 2 0 0 0 0 0

Normal sensitivity ranges, blue=31-50 dB, red=26-37 dB.s=Symptomatic, d=disease-haplotype carrier.

male parent carrying the disease gene and fivea female parent. Therefore the sex of theparent carrying the disease gene did not seemto influence the likelihood that a child with thedisease gene would be symptomatic.The results of clinical examinations are pre-

sented in Table 1. No individual identified as adisease haplotype carrier reported nightblind-ness in contrast with all symptomatic individu-als, who reported nyctalopia by their midteens. Typical fundus features of extensiveperipheral retinal degeneration were seen ineven the youngest examined symptomaticpatient (24 years) with macular atrophy,oedema, and secondary cataract formation inolder symptomatic individuals. Normal visualacuities and fundus examinations wererecorded for even the oldest asymptomaticdisease haplotype carrier (75 years). No sys-temic abnormality was identified as segregatingwith eye disease.

All symptomatic individuals assessed (24-61years of age) had elevated dark adapted thresh-old sensitivities for the whole 30° field testedwith matching areas ofrod and cone functionaldeficit (Table 2). Relative preservation of acentral island of vision was evident in youngersymptomatic individuals extending to approxi-mately 90 around fixation. In middle age thisisland was <30. In contrast, minimal thresholdelevations were detected in the central 30° ofasymptomatic disease haplotype carriers(within 7 dB of the normal limit). Abnormaldark adaptometry results were obtained fromall symptomatic patients tested with elevationof prebleach thresholds and elevated finalthresholds (Table 3). Prebleach thresholdelevation above 50 dB precluded dark adapto-metry in symptomatic individuals over 52 yearsof age. All symptomless disease haplotypecarrier individuals gave responses within 5 dBof normal mean values.

Electroretinographic responses were notdetectable (that is, <5 mV) in symptomaticindividuals over 30 years of age. Significantlyreduced electro-oculographic responses andERG changes indicative of a severe rod-conetype photoreceptor deficit were seen in allyounger symptomatic individuals (Table 4).Minor abnormalities in scotopic responses(within 34 mV of the lower normal limit withnormal implicit times) were also evident in twoasymptomatic disease haplotype carrierpatients (4-V-16, 24 years and 4-IV-5, 57years). Dramatic differences were thereforeseen in the results of field analysis and elec-trical responses of the youngest symptomaticpatients in comparison with those from eventhe oldest disease haplotype carriers. Thesedifferences were not attributable to age.

DiscussionMatching areas ofboth rod and cone functionalloss classify the phenotype seen in these familiesas R type (regional, type II), which contrastswith the widespread reduction in rod sensitivity-with relative sparing of cone function seen inD type (diffuse, type I) disease.22 23 Somerhodopsin mutations appear to cause D type

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Table 3 Dark adaptometry

Dark adapted Time to Time torod prebleach cone/rod prebleach

Genetic threshold, break thresholdPatient status elevation (dB) (minutes) (minutes) Dark adaption curve profile

Normal 0 9-11 30-453-V-2 x s 20 7 >45 Elevated final threshold

y 30 12 >45 relative to prebleach value4-IV-29 x s 22 6 >45 Elevated final threshold

y 40 13 >45 relative to prebleach value4-III-25 x d 8 9 35 Normal

y 9 9 354-III-5 x d 10 12 40 Normal

y 10 12 404-III-27 x d 10 6 42 Normal

y 15 6 424-III-28 x d 9 9 37 Normal

y 9 9 37

s=Symptomatic, d=disease-haplotype carrier, x=visual field locus (3,3), y=visual field locus (9,9).

functional loss,24-26 and others an R type lossassociated with an altitudinal distribution ofvisual field deficit unlike that seen here.18 27-34Regional functional loss has also been describedwith peripherin/RDS mutations althoughseverity was consistently related to age.35Detailed phenotype descriptions for pedigreeslinked to 7q, 8cen, and 17p are as yet unpub-lished. A phenotype with variable expressionand an R type pattern of deficit has beendescribed for the dominant retinitis pigmentosapedigree linked to chromosome 7p.12 However,a graded disease severity has been reported withmild, moderate, and severely affected indi-viduals. By extending the clinical study on thetwo families, the present study has identified a

large number of haplotype carriers who on

clinical examination and intensive investigationare essentially normal. This establishes thephenotype, R type functional deficit withbimodal expressivity, as a real phenomenon intwo large families that may be a unique featureof the 1 9q locus, and allows analysis of segrega-tion of disease in the pedigrees.To explain this unusual phenotypic expres-

sion, another influence in addition to theunderlying causative mutation mapping to 19qis most probably operating. This is unlikely tobe environmental since such an effect would beexpected to be dose dependent, and produce a

graded rather than the 'all or nothing' pheno-type seen here. In addition, despite extensive

research, environmental factors such as ambi-ent lighting have not been proved to have a

large influence on disease severity in retinitispigmentosa.3 36 A number of genetic mecha-nisms have been associated with variableexpression of disease phenotype. Anticipationdescribes disease severity related to increasingtrinucleotide repeat expansion as seen in fragileX syndrome37 and myotonic dystrophy.38Imprinting is often the basis for a phenotypeinfluenced by sex of the carrier parent.39Incomplete penetrance in certain retino-blastoma pedigrees has been attributed tomutations in gene promoter sequence40 or

'mild' germline mutations which reduce but donot eliminate tumour suppression proteinfunction.41 Anticipation, with severity relatedto position in a pedigree was not seen in thisstudy, and the sex of the disease gene carryingparent did not influence the likelihood of a

disease gene carrier being symptomatic. Also,the mechanism seen in retinoblastoma wouldnot explain the bimodal expressivity seen inthis study since incomplete penetrance of theretinoblastoma phenotype is usually associatedwith a relatively severe 'second hit' nullmutation in somatic cells.41 Such somatic cellmutations could not explain the panretinaldisease seen in retinitis pigmentosa.

Digenic inheritance describes the associa-tion of germline mutations in different genesthat result together in phenotype expressionbut cause minimal or no function deficit wheninherited individually.42 In retinitis pigmentosacases associated with digenic inheritance, thegene products (peripherin/RDS and ROM1)are structural proteins known to interrelatefunctionally at a cellular level. Such a mech-anism may imply that disease status in a par-ticular individual linked to gene mutation atthe 19q locus would be determined by thepresence of a second gene expressing a func-tionally related protein. This suggests that the19q mutation and another modulating gene

may encode related structural proteins, iontransport channel subunits, or related mem-

brane bound proteins. The protein products ofthese two mutations may also possibly beenzyme subunits. Mutations of enzyme codinggenes conventionally result in recessive

Table 4 Electrodiagnostic results

Electroretinography

Run 20Run 7 Run 18b wave b wave a wave b wave Run 31

Age EOGPatient (years) % amp imp amp imp amp imp amp imp amp imp

3-V-2 (s) 24 0 - 15 50 30 30 20 50 10 404-IV-i (s) 26 100/110 0 - 30 50 30 30 30 50 5 424-IV-29 (s) 25 137/135 0 - 10 46 7 30 18 50 10 474-IV-43 (s) 28 100/100 0 - 16 42 6 20 18 48 10 323-IV-5 (d) 57 195/210 45 120 60 50 50 30 220 50 35 313-V-13 (d) 33 120 100 60 42 120 15 280 45 30 303-V-16 (d) 24 141/161 55 95 60 48 41 25 220 51 25 354-III-25 (d) 25 370/335 140 90 120 46 80 23 270 45 25 304-III-27 (d) 57 200/218 160 100 200 44 60 22 260 44 35 304-IV-9 (d) 26 80 106 40 20 41 25 200 40 20 32Normal mean 199 100 153 47 132 22 384 45 43 29Normal limits 160 to 400 79 126 59 57 41 25 208 49 10 32

EOG=electro-oculogram. Electroretinogram run 7 (rod isolated), run 18 (cone dominant), run 20 (mixed photoreceptor),and run 31 (cone photoreceptor) correspond to a 'short protocol' regimen.'9 amp=Wave amplitude, imp=implicit time.Normal limits for electroretinographic responses refer to the normal mean -2 SD for wave amplitudes and the normal mean+2 SD for implicit times. s=Symptomatic, d=disease haplotype carrier.

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disease, but this well established dogma is notincontrovertible since a mutation in the 3 sub-unit of the enzyme phosphodiesterase has beenassociated with a dominant congenital station-ary nightblindness.43 The large number ofsymptomatic individuals from symptomlessdisease haplotype carriers would suggest thatthe second proposed mutation, derived fromthe unrelated spouse, may be common in thegeneral population. Since in itself this secondmutation is not associated with disease itcould be described as a gene polymorphism.However, it would be expected that if digenicinheritance explained the disease segregationin this study, then symptomatic individualswould be significantly more likely to havesymptomatic children than disease haplotypecarriers. This was not the case in these familiessince only 50% of children carrying the diseasegene derived from symptomatic individualswere themselves symptomatic compared with76% of children with the disease gene derivedfrom a disease haplotype carrier parent. Thisfinding may be explained if the second geneticinfluence in these families was in fact allelic tothe 1 9q mutation. Such allelic mutations,modifying disease expression have been identi-fied in Drosophila where the phenomenon istermed intragenic complementation.44 Also,an allelic, symptomless polymorphism of thespectrin gene, common in the population, hasbeen implicated as modulating the severity ofsymptoms in humans with a primary spectrinmutation causing hereditary haemolyticanaemia.45 This hypothesis will easily betestable once the 19q mutant gene is isolated.

Despite intensive work on cDNA libraries inmany laboratories, to date no research workerhas identified a retina specific gene on chromo-some 19. However, techniques used togenerate tissue specific libraries usuallyidentify genes that give rise to larger amountsof protein. the 19q gene product, althoughimportant to cell function, may not be a largecontributor to the protein content of retinalcells.46 Alternatively, the gene of interest maynot be retina specific. Although no systemicdisease was identified, the function of thedefective gene may be compensated for inother tissues in a way not possible in the retina.

In the past genetic counselling of suchfamilies has been difficult since clinical exami-nation and extensive investigation would notexclude the presence of the abnormal geneeven in late life. Although, as expected,roughly 50%/o of at risk individuals had thedisease haplotype the overall risk of beingsignificantly visually handicapped during aworking lifetime was only 31%. In addition,'minimal' disease in a parent did not imply anincreased likelihood of 'minimal' disease in off-spring. In these families accurate counselling istherefore dependent upon molecular genetichaplotype analysis.

1 Heckenlively JR. Retinitis pigmentosa. Philadelphia: JBLippincott, 1988.

2 Bundey S, Crews SJ. A study of retinitis pigmentosa in thecity of Birmingham. II. Clinical and genetic heterogeneity.J7Med Genet 1984; 21: 421-8.

3 Jay M. On the heredity of retinitis pigmentosa. Br JOphthalmol 1982; 66: 405-16.

4 Al-Maghtheh M, Gregory CY, Inglehearn CF, HardcastleA, Bhattacharya SS. Rhodopsin mutations in autosomaldominant retinitis pigmentosa. Hum Mutat 1993; 2:249-55.

5 Farrar GJ, Jordan SA, Kumar-Singh R, Inglehearn CF, GalA, Gregory CY, et al. Extensive genetic heterogeneity inautosomal dominant retinitis pigmentosa. In: HollyfieldJG, Anderson RE, LaVail MM, ed. Retinal degeneration.Clinical and laboratory applications. New York: Plenum,1994: 63-77.

6 Inglehearn CF, Carter SA, Keen TJ, Lindsey J, StephensonAM, Bashir R, et al. A new locus for autosomal dominantretinitis pigmentosa on chromosome 7p. Nature Genet1993; 4: 51-3.

7 Jordan SA, Farrar GJ, Kenna P, Humphries MM, SheilsDM, Kumar Singh R, et al. Localization of an autosomaldominant retinitis pigmentosa gene to chromosome 7q.Nature Genet 1993; 4: 54-8.

8 Blanton SH, Heckenlively JR, Cottingham AW, Friedman J,Sadler IA, Wagner M, et al. Linkage mapping of auto-somal dominant retinitis pigmentosa (RP1) to the peri-centric region of human chromosome 8. Genomics 1991;11: 857-69.

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11 Weleber RG, Carr RE, Murphey WH, Sheffield VC, StoneEM. Phenotypic variation including retinitis pigmentosa,pattern dystrophy, and fundus flavimaculatus in asingle family with a deletion of codon 153 or 154 of theperipherin/RDS gene. Arch Ophthalmol 1993; 111:1531-42.

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19 Arden GB, Carter RM, Hogg CR, Powell DJ, Ernst WJK,Clover GM, et al. A modified ERG technique and theresults obtained in X-linked retinitis pigmentosa. Br JOphthalmol 1981; 67: 419-30.

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