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Provision of Genetic Counselling for Patients with Retinal Dystrophy Prof. Graeme Black, Ms Georgina Hall Depts. of Ophthalmology and Clinical Genetics, Manchester Causes of childhood blindness Developed countries 30-50% childhood visual handicap is genetic Developing countries Africa Genetic S America India 21% 30% 30% Intrauterine 7% 2% 10% Perinatal Childhood 2% 34% 2% 37% 20% 12% Unknown 35% 30% 27% In developed countries, hereditary causes of blindness are the most important cause of childhood visual handicap Retinitis pigmentosa Symptoms • night blindness • constriction of peripheral visual field • later loss of central vision. Diagnosis • Progressive photoreceptor dysfunction • undetectable / reduced ERGs…… rod-mediated responses more severely affected than conemediated (i.e. rod-cone dystrophy). Retina • pigment in bone-spicule distribution. Retinitis pigmentosa 1 in 2500 Genetic condition Caused by single fault in one gene Deoxyribonucleic acid (DNA) and chromosomes 46 chromosomes Human chromosomes carry 20,000 to 30,000 genes Genes and Inheritance Chromosomes – – 22 identical pairs (“Autosomes”) 1 pair non- identical (“Sex Chromosomes”) XX=Female XY=Male Each chromosome carries 1 copy of gene (ie 2 copies of a gene per pair) What is a gene? Gene Protein A genetic disorder is caused by a single faulty gene Classification of RP Genetic – – – – Autosomal dominant X-linked Autosomal recessive Sporadic 10-15% 5-15% 30-50% 20-50% Onset – Birth : Leber congenital amaurosis – Childhood : many X-Linked, AR forms – Later onset: some AD forms Retinal manifestations (Symptoms or ERG define) – Cone-rod dystrophy – Rod-cone dystrophy – Cone dystrophy – Rod dystrophy Genes and RP Confusing – Faults in a large number of genes can cause RP and retinal degeneration Retinal dystrophies Hugely variable – onset outcome retinal findings – gene defect inheritance pattern Gene analysis tells us there are a large number of different forms - ?100 -200 Majority unclassifiable clinically Increasingly the precise genetic defect is known for many retinal degenerations…… or rather could be known Genetics and Ophthalmology in Manchester – 8 clinics per month – Run by clinical genetics alongside ophthalmology – Coworkers present – Held in clinical genetics unit / eye hopsital – 4-6 pts/clinic • Time • examine family members – Letters to patient Why have a genetic ophthalmic clinic at all? Large group of uncommon disorders – Unified approach – Diagnosis – Investigation – Counselling / FH Issues Pts referred for specialist opinion – ?correct diagnosis – ?geneticists cannot examine Clinician’s Objectives Diagnosis Risk estimation to family members Screening requirements Information Support Patient’s objectives (I think….) Treatment Prognosis Understanding Risks to family members (Children) – Prenatal diagnosis Presymptomatic diagnosis Perhaps our objectives are different…. Genetic Counsellors MSc genetic counselling Nurses – Additional training in genetics and counselling 300 in the UK Professional body (AGNC) Register (GCRB) – Code of ethics / conduct – Competency assessment What is “genetic counselling” Communication process Comprehend medical information Appreciate the hereditary impact Facilitate decision making (genetic testing, reproduction) in context of beliefs / family / cultural sensitvity Make best possible adjustment to genetic condition in family Why do people request genetic counselling? Diagnosis What is the cause? What will it mean for me? What are the risk to my children (other family members) What screening / tests / treatments available Nature of genetic information Patients may need to absorb a lot of new information that is often complex, abstract and difficult to grasp. Rapid advances in understanding of genetic basis of eye conditions. Heterogeneity – inheritance not clear cut. Counselling issues Over and above emotional impact of visual impairment (grief, loss) Burden / guilt Coping with risk / uncertainty Difficult decisions Impact on relationships / family dynamics Family coping styles / beliefs around visual impairment X-linked retinitis pigmentosa Boys affected late childhood / early teens Progressive No treatment Faulty gene on X chromosome Mothers are “carriers” – Half daughters will be carriers – Half sons will be affected XL Retinitis Pigmentosa 3 5 3 L dropped out of school, no exams Diagnosed XLRP aged 17 Anger and depression Isolated M denied diagnosis. “It hasn’t come from me” ?guilt XL Retinitis Pigmentosa 3 5 guilt 3 S Am I a carrier? Sister S wanted to know if she was a carrier New baby son J How would she feel if she were a carrier? How would she feel about her new baby? Would it affect decisions about further pregnancies? XL Retinitis Pigmentosa 3 5 3 L S J Testing children? J has a 50% risk of being affected? Should he be tested? Would it affect parenting / schooling? Benefits to S – relieving uncertainty Benefits to J? Meeting other family members Individual needs / decisions Confidentiality Counselling issues evolve with time Norrie’s disease X-linked Blind at birth Additional risks – 1/3 boys have learning difficulties – 1/3 boys develop deafness Norrie disease Chromosome 11p11.4 NDP gene Whole deletion incl Neighbouring MAO-A/B Family Tom Shock It’s my fault How will I cope / my family Sister about to start IVF treatment Burden of informing sister Sister 50% chance she is carrier Able to offer a blood test Options – Decide not to have a pregnancy – Continue with IVF (7/8 chance baby would not have Norrie’s) or test a pregnancy – Have pre-implantation genetic diagnosis Outcomes Sister not a carrier, able to continue with IVF without anxiety Tom doing extremely well. No learning difficulties or hearing problems. Very dedicated parents. Future concerns that daughter could be a carrier. Will not offer testing until she can make her own choice. Genetic testing for diagnosis: Can it be done? Genes identified for wide range of retinal dystrophies are known Genes able to be sequenced http://www.sph.uth.tmc.edu/Retnet/sum-dis.htm#D-graph Molecular Genetic Testing DNA sample (peripheral blood) Affected Individual / Obligate carrier Identify sequence variant – not present in normal population (monogenic disease) – In gene known to cause retinal disease What is the Position in 2011? Technological Advances mean tools more powerful than ever Many laboratories now offer diagnostic testing to the NHS http://www.mangen.co.uk/molecular_eye_and_rare_disease.asp adRP Genetic testing for retinal dystrophies is possible and available However testing is not universal Where it is clearly required, testing is usually available N = 1131 xlRP Why do patients require testing? Is the case for genetic testing persuasive? What is the evidence base? n = 840 Why develop genetic eye services? Inequity of services Gene discovery Patient demand Treatment trials Research to improve services Regard study Programme Grant Communication, accessibility Developing services for genetic counselling and testing Improving accessibility Hospital appointments by phone, email Written information – large print, email, braille, audio transcription Tactile genetic diagrams CCTV / software enlargement of diagrams Developing counselling services Mainly anecdotal evidence of counselling needs of families with inherited eye disease Requires robust research Evidence based MRC Framework for developing a complex intervention MRC framework Phase 1 – Modelling the intervention – Components Phase 2 – Exploratory trial Randomised control trial Aims Design a patient led care model for counselling and testing Develop evidence of patient benefit and “value” of improved counselling Phase 1 “Modelling” Qualitative interviews with families and healthcare professionals Snowballing Grounded theory PPI Important to involve patients / users in design, analysis and dissemination of research Regard Patient Advisory Group – Patients / users / experts – Leading charities (RNIB, BRPS, Guide Dogs, Macular Disease Society, NCBS, Genetic Alliance) – Patients – VI researchers and social workers PAG Regular meetings Formal presentations (teaching, training, updates) Small group work – Design methods Informal discussion Modify / improve design Regular email contact / updates and queries – E.g. Review of patient information prior to Ethics application – Publication of outputs included longer, more frequent meetings Advantages of patient involvement Motivation, extending knowledge base Relationships with pt support groups Focus work on improving patient care – National patient perspective – Timely, fitting with patient needs Collaboration – Genetic Alliance Route Maps, UK Vision strategy workshop Measuring benefit of genetic counselling Outcome measures Information recall “satisfaction” survey Depression / anxiety Genetic Empowerment scale – Feelings around the condition, impact on family, hope for future, empowerment to make decisions McAllister M et al, The Genetic Counseling Outcome Scale: a new patient-reported outcome measure for clinical genetics services Clinical Genet. 2011. Phase 2 Exploratory trial – Feasibility of intervention – Pilot outcome measures / develop estimates of effect size Economic “value” – Willingness to pay – Economic modelling to understand cost benefits of genetic testing Conclusions Retinal dystrophies important cause of VI in children/ young adults Emotional need related to – VI – Family / genetic / treatment needs Services patchily delivered Links to community support need to be improved Research into delivery and impact required