Ophthalmic Genetics, 28:9–15, 2007Copyright c© Informa HealthcareISSN: 1381-6810 (print) / 1744-5094 (online)DOI: 10.1080/13816810701199423

RESEARCH REPORT

Attitudes Regarding Predictive Testing for RetinitisPigmentosa

Eedy MezerDepartment of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto,Ontario, Canada

Riyana Babul-HirjiDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada

Richard WiseFaculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Mary ChipmanDepartment of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto,Ontario, Canada; Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; andDepartment of Public Health Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada

Lisa DaSilvaDepartment of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto,Ontario, Canada;

Mary RowellDepartment of Bioethics, The Hospital for Sick Children, Toronto, Ontario, Canada

Robin ThackrayDepartment of Social Work, University of Toronto, Toronto, Ontario, Canada

Cheryl T. ShumanDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada

Alex V. LevinDepartment of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto,Ontario, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto,Ontario, Canada; and Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Purpose: To assess attitudes towards predictive testing for autosomal dominant retinitis pig-mentosa (ADRP). Methods: A prospective questionnaire study of 46 affected adults and theiradult family members identified from pedigrees clearly consistent with ADRP or who had hadDNA-testing confirmation of ADRP before the study commenced. Results: High proportionsof unaffected siblings (73%) and patients (67%) agreed to prenatal testing. Patients agreed

26 September 2006.Address correspondence to Alex V. Levin, M.D., MHSc, FRCSC, Department of Ophthalmology, M158, The Hospital for Sick Children,

555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Tel: 416-813-6524; Fax: 416-813-6261; E-mail: alex.levin@sickkids.ca

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10 E. MEZER ET AL.

to prenatal testing. Patients agreed significantly more often than unaffected siblings that treat-ment should be available prior to initiating predictive testing. Psychoemotional distress wasreported in 57% of the affected adults and their family members in recollecting their own pre-dictive testing as children. Conclusions: ADRP families indicate a favorable attitude towardstesting presymptomatic children with counseling to lessen the psychological and social impactof results.

Keywords Predictive testing; autosomal dominant retinitis pigmentosa; presymptomatic genetictesting; prenatal genetic testing

INTRODUCTIONThe term retinitis pigmentosa (RP) describes a variety of

retinal dystrophies which have in common initial night visionloss, peripheral visual field constriction, characteristic funduswith optic atrophy, retinal vessel attenuation, and midperiph-eral pigmentary clumping (‘bone spicule pigmentation’) andprogressive deterioration of retinal rod and cone function onelectroretinography (ERG). The estimated prevalence is 1 in3500 worldwide.1 RP is known to occur as an autosomal dom-inant, autosomal recessive, mitochondrial, or X-linked disease.Age of onset and severity of symptoms vary with each genetictype, different mutation within any particular gene, and memberof the same family with the same mutation. With the exceptionof some specific entities such as Leber congenital amaurosis,there is usually a significant presymptomatic period followingbirth with the onset of symptoms ranging from early childhoodto late adulthood.2−6

During this latent period, diagnostic testing of affected in-dividuals can potentially be achieved by clinical examination,ERG, or DNA testing. However, results may be difficult to inter-pret. Clinical examination may reveal early retinal pigmentarychanges7 or subtle abnormalities in the macular internal limitingmembrane.8 These early changes may be so mild that counselingof the potentially affected individual must be tentative. Likewise,early diminishment of ERG responses may be difficult to inter-pret particularly in high myopes and children who are noncom-pliant with testing. Carriers may have mild ERG abnormalitiesand never develop RP.9 By ERG, they may be indistinguishablefrom individuals early in the course of RP who will eventuallysuffer visual loss.

Thirty-four mapped or cloned genes related to isolated retini-tis pigmentosa and 43 genes associated with syndromic/systemicdiseases with retinopathy have been identified.10 Direct muta-tion analysis, when possible, may provide definitive answersregarding which family members have inherited the mutation;however, expression can be variable and non-penetrance is occa-sionally observed. If a specific mutation is not identified in oneof the known RP-associated genes, linkage analysis may pro-vide information regarding transmission of the genetic region inquestion within a family. Accuracy of linkage is limited by thepossibility of recombination between genetic markers and thedisease gene. Despite difficulties and potential error of interpre-

tation, ERG, linkage, and mutation analysis are currently usedto identify adults and sometimes children as being affected withRP before symptoms arise. Currently, there is no effective RPtreatment.

There are potential and surmised risks to testing either posi-tive or negative for an adult-onset disorder. Testing positive foran adult-onset untreatable diseases has been reported to lead todepression (and even suicide), social discrimination, insurancediscrimination, and, for affected children, undesirable child-rearing practices such as limiting educational options.2,11,12

Testing negative, although generally favorable, may lead to anx-iety or depression.11,13−15 There may be feelings of guilt for notbeing affected like other family members. Persons testing nega-tive may also feel disappointed, realizing that they cannot fulfillplans, such as traveling more, after believing they would testpositive.16,17

Testing may be requested by asymptomatic adults wantingto know their status, parents desiring to know their child’s sta-tus, or physicians attempting to determine inheritance patternsand diagnosis. Reasons for pediatric testing include hypotheti-cal health benefits.2,12,14,18,19 However, careful weighing of po-tential benefits and harms should be undertaken.2,12,14,20 Theethical issues have been well discussed regarding a number ofocular and non-ocular conditions.21−29 The prototype for discus-sion has been Huntington disease (HD).17,30−43 In comparisonto HD, there is little literature regarding the issues surroundingRP predictive testing, especially in children.44−49

The current study specifically addresses attitudes towardspredictive testing for autosomal dominant RP, an untreatableoften late-onset disorder with a defined recurrence risk in theoffspring of affected adults.

MATERIALS AND METHODSTo identify registered affected individuals with RP prior to

1995 for invitation to participate in a prospective study, we per-formed a retrospective review of The Hospital for Sick Children(HSC) Ocular Genetics Programme (OGP) database and charts.Only those individuals from pedigrees clearly consistent withautosomal dominant RP (male-to-male transmission, more thanone generation affected) or who had confirmation of dominantRP on testing were included. Patients with other involved organsystems, such as deafness, were excluded to avoid confounding

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ATTITUDES REGARDING PREDICTIVE TESTING FOR RP 11

factors that might influence personal decisions concerning pre-dictive testing. Charts and pedigrees were reviewed to identifyaffected and unaffected family members who were previouslyexamined within the OGP. Subjects were 18 years of age orolder, fluent in English, and had the diagnosis of RP confirmedby examination by an OGP staff ophthalmologist and ERG. Toensure that the questionnaire items were clear and understand-able, a pilot study was conducted on 10 patients with syndromicRP (e.g., Usher or Bardet-Biedl syndrome, who were not knownto be mentally retarded). The study was approved by the HSCResearch Ethics Board.

All patients fulfilling the inclusion criteria were contacted bytelephone. If they agreed to participate, a questionnaire format-ted to their preference (regular print, large print, or Braille), aresearch consent form, a demographic questionnaire, and a coverletter were mailed. Visual function data were not collected as notall patients were examined in the OGP.

To ensure anonymity without precluding identification offamily members not previously examined at HSC, the coverletter and questionnaire instructed subjects to detach the demo-graphic questionnaire and consent form (after signature) andmail it in one envelope and to return the completed question-naire in another envelope. Prior to mailing, each questionnairewas given a coding number that allowed the researchers to assessthe accuracy of the respondent’s clinical information without vi-olating their anonymity.

The questionnaire assessed demographic variables, knowl-edge about RP, experience of having RP or being related tosomeone with RP, perceived advantages and disadvantages ofpredictive testing, and personal choice regarding predictive test-ing and prenatal testing for RP. The questionnaire was designedin keeping with other Human Subjects Committee-approved and-published instruments used for attitudinal surveys regardingpredictive testing for other diseases.38,50 The complete ques-tionnaire is available on request.

The questionnaire had seven parts. The first three sectionswere completed by all participants: anonymous background in-formation, questions about general screening (e.g., ‘I believe thatscreening tests which would tell someone they have a higher orlower chance of having a certain genetic condition should beused only if there is treatment’; answer: Likert scale 1-7), andgeneral RP knowledge questions (e.g., ‘Which factor do youbelieve is the strongest cause of RP’; answer multiple choice:genes, sunlight, virus, stress, other). The next three sectionswere each completed by different family members (proband,unaffected siblings, or unaffected parents) and addressed thecircumstance of RP diagnosis and attitudes towards the predic-tive testing of children of affected respondents or respondentswho were parents of affected children. Siblings of affected in-dividuals were asked about prenatal testing. The last section,completed by all participants, investigated attitudes regardingthe molecular diagnosis of respondents in different settings (e.g.,‘If in the future a blood test were to become available whichwould make it possible to determine the inheritance of RP in

your family and to determine whether or not you carry the genedefect for RP with complete certainty, i.e., 100%, would youwant to use the test for yourself?; Multiple choice answer yes,no, or do not know. Please explain’). Data for the last sectionare not reported herein as no conclusion could be drawn fromthe statistical or clinical data analysis.

Statistical AnalysisGraphPad InStat version 3.06 for Windows (GraphPad Soft-

ware, San Diego, CA, USA, www.graphpad.com) was used forthe statistical analyses. Continuous variables were comparedusing t-tests; categorical variables were compared using chi-squared tests for Fisher’s exact test if small numbers warrantedthis. To compare responses concerning intentions to have chil-dren in the future, logistic regression was used to control forwhether respondents already had children.

RESULTSA total of 46 (83%) of 54 mailed questionnaires were com-

pleted and returned (Table 1). Most of the respondents were mar-ried (59%) and had at least one child (63%). The study groupincluded 27 individuals (59%) affected with RP, 12 (26%) unaf-fected relatives, and seven (15%) individuals unsure of their sta-tus (excluded from any comparative analysis). Fifteen of the 27affected subjects were probands; the remaining individuals in-cluded affected parents or siblings of probands. Affected individ-uals were more likely than their unaffected relatives to endorseRP screening tests if there was available treatment (Table 2).

TABLE 1Demographic data of respondents

Demographic Number (% of total Subgroup number (%data respondents) of total respondents)

Male 20 (43%) N/AMarried 27 (59%) N/AAt least one

child29 (63%) N/A

Affection status 27 (59%)affectedindividual

15 (31%) affectedparents ofprobands

12 (28%) affectedparents orsiblings ofaffectedindividual

Unaffectedsiblings ofan affectedindividual

12 (26%) 7 (15%) tested

Unsure of status 7 (15%)

N/A, not available.

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12 E. MEZER ET AL.

TABLE 2Attitudes regarding predictive testing for retinitis pigmentosaa

Unaffected Affectedb

Statement (n = 12) (n = 27) p valuec

Screening tests should be used only if there is a treatment availablefor the genetic condition being screened for

2.67 ± 1.97 4.41 ± 2.27 0.0275

All at-risk individuals should participate in a screening test if treatment isavailable upon early diagnosis

5.75 ± 1.22 6.44 ± 1.19 0.1056

Healthcare workers administering the screening tests should bewell-informed and educated about the pros/cons of such tests

6.17 ± 1.19 6.70 ± 1.20 0.21

The individual undergoing a screening test should first be educated andcounseled about the nature of the test

6.67 ± 0.49 6.67 ± 0.96 1

Insurance companies should have access to the results of a person’s geneticscreening test

2.75 ± 2.05 3.00 ± 2.04 0.7263

There should be a minimum age requirement of 18 for genetic screeningtests

2.75 ± 2.01 3.52 ± 1.89 0.2567

a1 = very strongly disagree. . . 7 = very strongly agree.bProbands, affected parents, and affected siblings.ct-test, two-tailed.

Although both groups strongly agreed that all at-risk individu-als should be tested if treatment was available, affected subjectsagreed more strongly than unaffected relatives. Neither groupwas in favor of a minimum age requirement of 18 predictivetesting, but affected individuals tended on average to be equiv-ocal about this sentiment.

There was no statistically significant difference (p > 0.05)between opinions of affected and unaffected individuals regard-ing prenatal testing for RP (Table 3). Similar high proportionsof unaffected (8/11, 73%) and affected subjects (12/18, 67%)agreed to prenatal testing. Both groups also had very similaranswers regarding pregnancy termination if prenatal RP test-ing was positive (Table 3): approximately 25% uncertain, andamong those who were certain, only one affected person wouldabort the pregnancy.

TABLE 3Hypothetical situations

Unaffected Affecteda

Hypothetical situation Response (n = 12) (n = 27) p valueb

If prenatal testing were available, which wouldindicate whether or not the unborn baby had thegene for RP, would you want to use such a test?

Yes 8 (67%) 12 (44%)No 3 (25%) 6 (22%) 0.13Don’t know 1 (8%) 9 (33%)

If this prenatal test showed that the unborn babyhad the gene for RP (i.e., will eventually showsymptoms for RP), what would you want to do?

I would want to complete thepregnancy

9 (75%) 19 (70%) 1.00

I would want to abort the pregnancy 0 (0%) 1 (4%)I am unsure 3 (25%) 7 (26%) 1.00

aProbands, affected parents, and affected siblings.bFisher’s exact test, two-tailed.

Thirty-four children from 14 families, in whom at least oneparent had RP, had predictive testing. The children were amongthe 46 respondents. Twelve tested positive and 11 negative. Forthe remaining 11, either the physician was uncertain (n = 6)or the parent did not know the results (n = 5). For most of thechildren tested (79%), parents discussed the result with the child.For 10 families with 21 children, parents described the emotionalresponses perceived in their child after receiving results, rangingfrom 5% reporting guilt to 57% reporting fright (Table 4).

DISCUSSIONPredictive testing for genetic diseases is becoming increas-

ingly available as molecular genetic techniques are refined andmore disease-causing genes are identified. Although there areclear benefits to testing for conditions where a positive result

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ATTITUDES REGARDING PREDICTIVE TESTING FOR RP 13

TABLE 4Children’s reactions to results of predictive testing

Number of childrena

Emotional response (%)

Fright 12 (57.1)Disappointment 9 (42.9)Anger 9 (42.9)Confusion 8 (38.1)Anxiety 6 (28.6)Relief 6 (28.6)Guilt 1 (4.8)

aTotal number tested children: 34. Some children reported to expe-rience more than one adverse response.

leads to interventional strategies, the use of predictive testing foruntreatable disorders is controversial, particularly when testingchildren for adult-onset disorders. Literature is scarce regardingpredictive testing of children for adult-onset untreatable ocu-lar disease. We examined attitudes about predictive testing infamilies affected by one such disorder, autosomal dominant RP.Results of our study indicate that unaffected and affected mem-bers of these families share some common perspectives in favorof predictive testing. However, affected subjects tend to be moreconservative and reluctant to pursue genetic testing of children.

Many articles have been published on adult predictive testingfor genetic conditions with HD serving as a paradigm.38,39,41−43

The literature also addresses, to a lesser degree, testingof children for both untreatable (e.g., Huntington disease,amyotrophic lateral sclerosis)41,49 and partially treatable disor-ders (hypercholesterolemia).28,51,52 Little is written about pre-dictive testing of children for adult-onset untreatable disorders.

The 1994 Working Party of the United Kingdom ClinicalGenetics Society wrote, “Despite our judgment that it is wise toavoid predictive tests in childhood . . . if the child stands to gainsome health benefit from predictive testing, then it is obviouslygood practice to make the testing available.”12 Although no treat-ment is available, whether or not there are potential health ben-efits from predictive testing for RP is unknown. Regarding RPpredictive testing, these authors found a wide range of opinionamongst various medical professionals.12 Although only 15%of pediatricians opposed predictive RP testing, approximately50% of geneticists would not offer such testing to children.

To our knowledge, there have been only two prior reportsregarding attitudes towards RP predictive testing. Furu andcoworkers used a questionnaire to investigate attitudes towardsprenatal diagnosis of 182 patients with clinical features of RP,136 relatives of RP patients, 11 patients with choroideremia,12 non-carrier relatives, and 14 choroideremia carriers.48 Ap-proximately 65% of the patients with RP and their relatives hadpositive attitudes about prenatal testing for these disorders (nosignificant difference between the two groups), although only30% would favor abortion of affected fetuses. Approximately

20% recommended testing children. Favorable feelings aboutabortion correlated positively with increased severity of RPin affected respondents. Significant methodological problemsincluded exclusion of blind patients, skewed age of respon-dents, very inaccurate understanding of inheritance patterns byrespondents, the small number of subjects affected with choroi-deremia, and the very low response rate (35%). Issues beyondprenatal testing were not explored.

In a letter, Pawlowitzki and coworkers quoted an attitudi-nal questionnaire survey of 414 patients with RP (inheritancepatterns not specified).49 Sixty-one percent of the respondentsfelt there were potential dangers in molecular diagnostics, while90% felt there were potential advantages with over 80% citingsuch areas as potential for treatment, accurate diagnosis, earlierdiagnosis, or carrier identification. No comment was made re-garding presymptomatic identification of affected individuals,although 64% supported prenatal testing. Only 27.3% stronglysupported prenatal diagnosis for pregnancy termination.

In our study, more unaffected individuals (67%) supportedprenatal testing than affected patients (44%), but this was notstatistically significant. Seventy-five percent of the unaffectedsubjects and 70% of our affected cohort favored continuing preg-nancies if the tests showed that the fetus had the gene mutation.This paradox in favor of prenatal testing despite a wish to con-tinue pregnancies even if gene tests were positive supports thefindings of Furu and Pawlowitzki and has also been observedwith nonvisual disorders.41,48,49,53 Neither religious persuasionnor timing of pregnancy was examined in our study. The paradoxmay be explained by the high degrees of uncertainty regardingpregnancy termination due to the need to weigh multiple factorsat the time a decision must be made and the variability in clinicalexpression.53

We found affected patients were significantly more likelyto support predictive testing than unaffected relatives: a findingsimilarly found in patients undergoing predictive testing for HD.Even when tangible benefits from predictive testing (e.g., med-ical treatment) are not available, individuals may benefit.34 Ineditorial commentaries, three ophthalmologists who routinelydeal with patients affected with RP debated the use of predictivetesting for autosomal dominant RP.45 One author emphasizedthat molecular testing provides evidence for a risk factor, butdoes not imply the patient will definitely develop the disease.Diagnosis remains clinical and this must be explained to thefamily. Another author argued that the patient should enter thedecision-making process when old enough to do so, because RPis untreatable. The remaining author emphasized that researchparticipation can be therapeutic for a family rather than sayingthat nothing can be done. If the child is not expected to receiveimmediate proven medical benefits, some authors advocate de-laying the tests.2

The number of children (n = 34) presymptomatically testedfor RP in our study may indicate easy access to testing and/ora strong desire of families to have testing conducted. This alsosuggests that families may perceive benefits34,45 even though

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14 E. MEZER ET AL.

testing may be associated with adverse psychosocial outcomes.Indeed, 57% of the tested children reportedly experienced ad-verse reactions after receiving results, indicating the potential forsignificant harm of testing. Reactions may in part arise from themanner in which test results were communicated to the child.Factors contributing to outcome include whether parents or ahealthcare professional conveyed the information, whether thediagnosis was fully disclosed, and other life experiences of thechild. Other potential outcomes include influence on career se-lection and anticipatory low-vision intervention. Those affectedwith RP were significantly more supportive of testing than un-affected individuals, should treatment be available.

Because our sample size was relatively small, larger and long-term studies are needed. Extrapolation from other genetic dis-orders may not be appropriate for patients with RP as otherillnesses may carry different inheritance patterns, rates of pro-gression, and risks for morbidity and mortality.

Prior to this study, patients (including those enrolled as sub-jects herein) did not routinely receive information about the prosand cons of predictive testing. Before deciding to proceed withpredictive testing for autosomal dominant RP, we now offer ge-netic counseling so that the family and children are optimallyinformed of the potential risks and benefits including some shar-ing of the results of this study as it may be useful to those consid-ering predictive testing. We are hopeful that this approach mayhelp caretakers make more informed decisions about whether ornot to proceed with predictive testing, assist our ocular geneticsteam in planning a management strategy, and reduce anxiety andunwanted negative sequelae among children who are tested.

ACKNOWLEDGEMENTSWe are grateful for the administrative contributions of our

Research Assistants Enza Perruzza and Erica Bell. Support wasprovided in part by Brandan’s Eye Research Fund. The author(AVL) had full access to all of the data in the study and takesresponsibility for the integrity of the data and the accuracy ofthe data analysis.

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