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Genetic Testing of Adults with Intellectual Disability: why do it? Dr Jana de Villiers Consultant Psychiatrist for the Fife Forensic Learning Disability.

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Presentation on theme: "Genetic Testing of Adults with Intellectual Disability: why do it? Dr Jana de Villiers Consultant Psychiatrist for the Fife Forensic Learning Disability."— Presentation transcript:

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

2 Intellectual disability Health Condition? Social/Educational issue?

3 National Institute of Health Funding (millions of $)

4 Metasyndrome

5 Aetiology of Intellectual Disability Neurotoxic Nutritional Metabolic Infectious Genetic

6 Aetiology of Intellectual Disability Neurotoxic Nutritional Metabolic Infectious Genetic

7 Gene Molecule Cell System Behaviour Genotype Intermediate Phenotypes Classical diagnostic phenotypes Whole genome scan Proteomics Electrophysiology Neuroimaging Cognitive function tests

8 Trisomy 21

9 Chromosome banding

10 Fluorescent in-situ hybridization

11 Patient DNANormal 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 with 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

12 60mer oligo from Duplicated Region 60mer oligo from 60mer oligo from Deleted Region Microarray Slide

13 Sample result

14 Increasing diagnostic yields Conventional cytogenetics3-4% Subtelomere FISH5-7% Clinically relevant CNVs on microarray 15-20%

15 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

16 The message that a prior “negative genetic workup” done 20 or more years ago is not sufficient to have excluded genetic causes of intellectual disability needs to be conveyed.

17 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 of LD psychiatrists and Clinical Geneticists regarding the value and appropriateness of genetic testing in adults with LD

18 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-structured interviews with eight LD psychiatrists and two Clinical Geneticists

19 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 of 617 (22%) tested –19 of 138 (14%) had a genetic diagnosis –Therefore in Borders 3% of patients have a known genetic diagnosis

20 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 be Some LD psychiatrists have never requested genetic testing in a patient

21 Clinical Geneticist 1 “I think it can be useful for the adults themselves sometimes to actually get a name for the problems that they’ve had.”

22 Clinical Geneticist 2 “ I think it is easy to underestimate how important it is to people themselves to have a diagnosis.” “For children there is a very good service but adults perhaps don’t get quite the same level of genetic and dysmorphology input that they should do.”

23 LD Psychiatrist 4 “The disadvantages of genetic testing are that you might find things you’d…rather wish you didn’t know”

24 LD Psychiatrist 5 “…it might be satisfying for doctors and clinicians to know what’s what, but really is it of any benefit to that individual or their family?”

25 Why test? Four in ten patients with ID due to chromosome abnormalities have no dysmorphic features

26 Why test? Improved patient management Surveillance for known complications/associated abnormalities Prognosis Support network for families

27 Why test? “There is substantial value in knowing”

28 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 behavioural problems, anxiety and ritualistic behaviours Dx with Autism aged 10

29 Case study IQ=59 aged 10 Referred to Children’s 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

30 Case study Grommets as a child – ongoing hearing impairment Severe gastro-oesophageal reflux – had surgery

31 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 schizophrenia –Associated with hearing impairment, oesophageal pouches and cardiac abnormalities

32 Case study Assessed by Cardiologist: showing dilated aortic root requiring regular monitoring and surgery if dilation increases Prescribed losartan to slow progression of dilation

33 Why test? Treatment

34 Fragile X

35 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)

36 Fragile X Diagnosis has significant implications for the wider family Premutation (50-200 CGG repeats) associated with neurodegenerative fragile X tremor-ataxia syndrome (FRAXTAS) Female premutation carriers have increased rates of premature ovarian insufficiency

37 Fragile X Specific interventions required: –Cardiac monitoring if mitral valve stenosis or aortic root dilatation –Epilepsy –Visual complications (squint) –Hearing impairments

38 Fragile X Social anxiety common, with gaze aversion and odd social interactions Self-injury – biting over base of the thumb

39 Treatment of Fragile X mGluR5 antagonists

40 “[Making a diagnosis] allows us to move beyond the stage occupied by 19 th - century physicians, who could only classify and understand physical illness in terms of presenting features rather than cause…”

41 “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 social contributors to developmental…disabilities and how thus they can be better addressed, treated and ameliorated.”

42 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 Down’s syndrome 3 with deletions on array CGH



45 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; 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

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