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

Intellectual disabilityHealth

Condition?

Social/Educational issue?

National Institute of Health Funding

(millions of $)

Metasyndrome

Aetiology of Intellectual Disability

NeurotoxicNutritional

MetabolicInfectious

Genetic

Aetiology of Intellectual Disability

NeurotoxicNutritional

MetabolicInfectious

Genetic

Gene

Molecule

Cell

System

Behaviour

Genotype

IntermediatePhenotypesClassical diagnostic phenotypes

Whole genome 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 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

60mer oligo from 60mer oligo from Duplicated RegionDuplicated Region

60mer oligo from 60mer oligo from Deleted RegionDeleted Region

Microarray SlideMicroarray Slide

Sample result

Increasing diagnostic yields

Conventional cytogenetics

3-4%

Subtelomere FISH 5-7%

Clinically relevant CNVs on microarray

15-20%

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 workup”

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 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-structured 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 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 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 they’ve had.”

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.”

LD Psychiatrist 4

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

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?”

Why test?

• Four in ten patients with ID due to chromosome abnormalities have no dysmorphic features

Why test?

• Improved patient management• 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 behavioural problems, anxiety and ritualistic behaviours

• Dx with Autism aged 10

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

Case study

• Grommets 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 schizophrenia– 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

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)

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

Fragile X

• Specific interventions required:–Cardiac monitoring if mitral valve stenosis or aortic root dilatation

–Epilepsy–Visual complications (squint)–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 classify 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 social contributors to developmental…disabilities 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 Down’s syndrome

• 3 with deletions on array CGH

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