Recent findings from ASD genetic studies: Is there an opportunity for clinical genetic

testing?

Dr Jeremy Parr

Senior Lecturer and Consultant

Paediatric Neurodisability

Overview

• Autism and the autism spectrum

• Historical context: ASD genetics research

• Recent findings regarding copy number variants

• Parents opinions about clinical genetic testing

• Are we ready for clinical genetic testing in the NH S?

Autism Spectrum Disorder (ASD)

A neurodevelopmental disorder; difficulties from earlychildhood

Core autism, Asperger syndrome, atypical autism, ASD etc

Social communication difficulties, and repetitive,stereotyped and/or rigid behaviour; positives

Common; learning disability, epilepsy, regression

A spectrum; the Broader Autism Phenotype

Twin, family and genetic studies; genetic cause; environment?

ASD genetics research: 1970-2007

Monozygotic twins likely to be concordant for ASD; DZ twins;case reports and then series

Recurrance rate in siblings; family history data show BroaderAutism Phenotype in non ASD relatives

15% of children with autism have another diagnosis; e.g.FRAX, Down syndrome

Remainder related to genetic and ‘other’ factors -‘autism susceptibility genes’

Consortia: No evidence for a common causal variant after 10years; but inadequate sample sizes and statistical power

Copy number variation and array comparative genomic hybridisation

• Copy number variants are areas of genetic code in which deletions and duplications are ‘repeated’, leading to alteration of gene function

• We all have CNVs; some CNVs cause conditions

• aCGH will replace karyotyping in 2012 (2011)

• Allows us to identify much smaller deletions and duplications than karyotyping – we can identify copy number variants

Summary

Some medical disorders are associated with ASD (15%)

CNVs that cause ASD are individually rare (<1%); together, cause 15% of ASD

16p11 variants – 1% of children with ASD

Some people with ‘causal’ CNVs don’t have ASD

Causal ASD CNVs also associated with schizophrenia and other conditions

Array technology and potentially pathogenic CNVs make clinical genetic testing a possibility

(Sensitivity and specificity, and positive and negative predictivevalue)

An ASD clinicians perspective

Many parents in clinic ask about the cause of their child’s difficulties

Some know about ASD and genetics

Some ask about chances of having another child with ASD (10%)

Clinicians are used to testing associated with medical conditions

Less used to testing in the face of uncertainty

Use of cCGH in clinical practice

Array technology and potentially pathogenic CNVs make clinical genetic testing a possibility....but do we know enough yet to be doing it

(Sensitivity and specificity, and positive and negative predictivevalue)

Parents opinions and those of people with ASD – do they want testing?

For example, Autism Genome Project database includes 5 835 families; very little knowledge about what parents want

‘We know that autism is not a disease, and we oppose any attempts to "cure" someone of an Autism spectrum condition, or any attempts to make them 'normal' against their will’

Some people with ASD, relatives, clinicians, ethicists concerned about testing – others see as an opportunity

Speed of translation in healthcare; private genetics testing; impact for families if results not in appropriate context

High risk for community is polarisation; the elephant in the room

Individual opinions vs. a large group; difficulty for policy makers

Survey: Understanding parents’ opinions about clinical genetic testing

Jeremy Parr

Annette Hames

Rebecca Alegbo

Alex Henderson

Tracy Finch

Janice McLaughlin

Deborah Garland

Responses

381 parent responses; 38% of families (293)

84 families in which responses from both parents received

90% singleton families; 10% families with 2 or more children with ASD

Results

77% yes; 8% no; 15% unsure

If their child was found to have gene(s) that caused ASD:

• 78% of these parents would have the test themselves; 14% no; 8% unsure (27% to help explain their own difficulties)

• 53% of these parents would have children without ASD tested; 26% wouldn’t; 21% unsure

If it were available, 54% of parents would have a test beforehaving another child

24% no

22% unsure

Parents of children with single words / no speech significantlymore likely to want genetic testing before a pregnancy thanthose with short sentences / fluent speech (p=0.005)

Themes from free text re ‘why do you think that?’

• Preparation and choice (33%)

• Makes no difference (17%)

• Negative feelings about ASD (10%)

• Harm (8%)

• Positive feelings about ASD (6%)

Are we ready for clinical genetic testing? Sort of. ...

Technology allows testing

Some parents interested

We need to know more about ‘causal variants’

Implications for parents and people with ASD?

Value of testing for families and clinicians?

Implications for NHS? GPs? Paediatricians? Clinical Genetics?

Thank you