1、Genetic Testing of Adults with Intellectual Disability: why do it?,Dr Jana de Villiers Consultant Psychiatrist for the Fife Forensic Learning Disability Service 14 June 2013,Intellectual disability,Health Condition?,Social/Educational issue?,National Institute of Health Funding (millions of $),Metas
2、yndrome,Aetiology of Intellectual Disability,Neurotoxic,Nutritional,Metabolic,Infectious,Genetic,Aetiology of Intellectual Disability,Neurotoxic,Nutritional,Metabolic,Infectious,Genetic,Gene,Molecule,Cell,System,Behaviour,Genotype,Intermediate Phenotypes,Classical diagnostic phenotypes,Whole genome
3、scan,Proteomics,Electrophysiology,Neuroimaging,Cognitive function tests,Trisomy 21,Chromosome banding,Fluorescent in-situ hybridization,Patient DNA,Normal Control DNA,Mix Equimolar Amounts of Labelled DNA,Patient:Control ratio = 1,Patient:Control ratio 0.5:1 i.e. deletion in Patient DNA,Label DNA wi
4、th different fluorescent dyes,Apply DNA mix to glass slide with high-density array of different DNA probes with known location in the human genome,Patient:Control ratio 1.5:1 i.e. duplication in Patient DNA,60mer oligo from Duplicated Region,60mer oligo from Deleted Region,Microarray Slide,Sample re
5、sult,Increasing diagnostic yields,Genetics of intellectual disability,Most important single cause remains Down syndrome Most common identifiable inherited cause of ID (and of autism) is Fragile X Submicroscopic deletions and duplications equally frequent,The message that a prior“negative genetic wor
6、kup”done 20 or more years ago is not sufficient to have excluded genetic causes of intellectual disability needs to be conveyed.,Project,To ascertain what proportion of adults with LD known to services in Lothian and Borders have had genetic testing (and the diagnostic yield) To determine the views
7、of LD psychiatrists and Clinical Geneticists regarding the value and appropriateness of genetic testing in adults with LD,Method,Adults with LD known to services in Lothian and Borders in 2009 cross-matched with data base of patients tested at WGH since 1994 Diagnostic yield calculated Semi-structur
8、ed interviews with eight LD psychiatrists and two Clinical Geneticists,Results,Lothian 1211 of 2706 (45%) tested 170 of the 1211 tested (14%) had a genetic diagnosis Therefore in Lothian 6% of patients have a known genetic diagnosis (compared to reported rates of 20% from recent studies) Borders 138
9、 of 617 (22%) tested 19 of 138 (14%) had a genetic diagnosis Therefore in Borders 3% of patients have a known genetic diagnosis,Interviews,5 out of 8 LD psychiatrists did not think genetic testing should be a routine part of assessment in adults with LD Both clinical geneticists felt that it should
10、be Some LD psychiatrists have never requested genetic testing in a patient,Clinical Geneticist 1,“I think it can be useful for the adults themselves sometimes to actually get a name for the problems that theyve had.”,Clinical Geneticist 2,“I think it is easy to underestimate how important it is to p
11、eople themselves to have a diagnosis.”“For children there is a very good service but adults perhaps dont get quite the same level of genetic and dysmorphology input that they should do.”,LD Psychiatrist 4,“The disadvantages of genetic testing are that you might find things youdrather wish you didnt
12、know”,LD Psychiatrist 5,“it might be satisfying for doctors and clinicians to know whats what, but really is it of any benefit to that individual or their family?”,Why test?,Four in ten patients with ID due to chromosome abnormalities have no dysmorphic features,Why test?,Improved patient management
13、 Surveillance for known complications/associated abnormalities Prognosis Support network for families,Why test?,“There is substantial value in knowing”,Case study,18 year old male Charged after exposing genitals to children in a public park Seen by Child and Adolescent Services from age 5 due to beh
14、avioural problems, anxiety and ritualistic behaviours Dx with Autism aged 10,Case study,IQ=59 aged 10 Referred to Childrens Panel aged 14 after exposing genitals over webcam on MSN to peers Father diagnosed with Gulf War Syndrome and mother with depression Excess alcohol use from age 16,Case study,G
15、rommets as a child ongoing hearing impairment Severe gastro-oesophageal reflux had surgery,Case study,Genetic testing aged 18 DiGeorge syndrome (22q11 deletion) Associated with autism, anxiety, depression and impairments of both expressive and receptive language 20-30X increased risk of schizophreni
16、a Associated with hearing impairment, oesophageal pouches and cardiac abnormalities,Case study,Assessed by Cardiologist: showing dilated aortic root requiring regular monitoring and surgery if dilation increases Prescribed losartan to slow progression of dilation,Why test?,Treatment,Fragile X,Fragil
17、e X,Caused by triplet repeat (200 CGG) on tip of X chromosome long arm Frequently normal appearance Mild intellectual disability (often misattributed to subcultural or psychosocial factors),Fragile X,Diagnosis has significant implications for the wider family Premutation (50-200 CGG repeats) associa
18、ted with neurodegenerative fragile X tremor-ataxia syndrome (FRAXTAS) Female premutation carriers have increased rates of premature ovarian insufficiency,Fragile X,Specific interventions required: Cardiac monitoring if mitral valve stenosis or aortic root dilatation Epilepsy Visual complications (sq
19、uint) Hearing impairments,Fragile X,Social anxiety common, with gaze aversion and odd social interactions Self-injury biting over base of the thumb,Treatment of Fragile X,mGluR5 antagonists,“Making a diagnosis allows us to move beyond the stage occupied by 19th-century physicians, who could only cla
20、ssify and understand physical illness in terms of presenting features rather than cause”,“We have moral and ethical as well as scientific and clinical responsibilities towards our clients and their families to evolve our understanding of the complex interactions between biological, psychological and
21、 social contributors to developmentaldisabilities and how thus they can be better addressed, treated and ameliorated.”,Current case load,8 out of 48 patients have had genetic testing All males with mild LD and forensic needs 1 patient with XYY (Klinefelters) 1 patient with Downs syndrome 3 with dele
22、tions on array CGH,References,De Villiers J, Porteous M. Genetic testing of adults with intellectual disability. Psychiatrist (2012) 36, 409-413. Li MM, Andersson HC. Clinical Application of Microarray-Based Molecular Cytogenetics: An Emerging New Era of Genomic Medicine. Journal of Pediatrics 2009;
23、 Vol 105, No 3: 311-317. Salvador-Carulla and Bertelli, Psychopathology 2008; 41:10-16 Turk M, Fragile X syndrome: lifespan developmental implications for those without as well as with intellectual disability. Current Opinion in Psychiatry 2011; 24:287-397. Vassos E, Collier DA and Fazel S. Systematic meta-analyses and field synopsis of genetic association studies of violence and aggression. Molecular Psychiatry, April 2013,
