genetic testing of adults with intellectual disability: why do it? dr jana de villiers consultant...
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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
Service14 June 2013
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Intellectual disabilityHealth
Condition?
Social/Educational issue?
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National Institute of Health Funding
(millions of $)
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Metasyndrome
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Aetiology of Intellectual Disability
NeurotoxicNutritional
MetabolicInfectious
Genetic
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Aetiology of Intellectual Disability
NeurotoxicNutritional
MetabolicInfectious
Genetic
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Gene
Molecule
Cell
System
Behaviour
Genotype
IntermediatePhenotypesClassical diagnostic phenotypes
Whole genome scan
Proteomics
Electrophysiology
Neuroimaging
Cognitive function tests
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Trisomy 21
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Chromosome banding
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Fluorescent in-situ hybridization
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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 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
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60mer oligo from 60mer oligo from Duplicated RegionDuplicated Region
60mer oligo from 60mer oligo from Deleted RegionDeleted Region
Microarray SlideMicroarray Slide
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Sample result
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Increasing diagnostic yields
Conventional cytogenetics
3-4%
Subtelomere FISH 5-7%
Clinically relevant CNVs on microarray
15-20%
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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
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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.
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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
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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
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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
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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
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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.”
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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.”
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LD Psychiatrist 4
“The disadvantages of genetic testing are that you might find things you’d…rather wish you didn’t know”
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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?”
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Why test?
• Four in ten patients with ID due to chromosome abnormalities have no dysmorphic features
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Why test?
• Improved patient management• Surveillance for known
complications/associated abnormalities
• Prognosis• Support network for families
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Why test?
• “There is substantial value in knowing”
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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
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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
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Case study
• Grommets as a child – ongoing hearing impairment
• Severe gastro-oesophageal reflux – had surgery
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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
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Case study
• Assessed by Cardiologist: showing dilated aortic root requiring regular monitoring and surgery if dilation increases
• Prescribed losartan to slow progression of dilation
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Why test?
• Treatment
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Fragile X
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Fragile 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)
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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
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Fragile X
• Specific interventions required:–Cardiac monitoring if mitral valve stenosis or aortic root dilatation
–Epilepsy–Visual complications (squint)–Hearing impairments
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Fragile X
• Social anxiety common, with gaze aversion and odd social interactions
• Self-injury – biting over base of the thumb
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Treatment of Fragile X
• mGluR5 antagonists
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“[Making a diagnosis] allows us to move beyond the stage occupied by 19th-century physicians, who could only classify and understand physical illness in terms of presenting features rather than cause…”
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“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.”
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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
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ReferencesDe 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; 41:10-16Turk 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