Can view other patients

Also search Pubmed, google,

etc

Interpretation depends on…

• Size• Location• Genes involved• Previously reported patients• Documented pathogenic CNV region or documented ‘benign’ CNV

region• Tools: genome browser, databases of variants• Pubmed/Literature review• Family history/structure

– How does the variant segregate?– Are parents affected?– Could this be a ‘susceptibility locus’

These are the 4 possible outcomes of every array, which need to be discussed in the consent

A good factsheet for consenthttp://www.genetics.edu.au/Publications-and-Resources/Genetics-Fact-Sheets/

FactSheet6A

Array for prenatal abnormality (with

consent)

Pathogenic CNV – likely answer

Clearly defined microdel/dup

syndrome

Based on size and location

Counsel +/- genetics involvement, especially for

recurrence information

Consider parentals (unlikely if severe)

Benign CNV – Unlikely answer

Based on literature/ population CNV

databases

Maybe also found in a normal parent

Unlikely answer – Empiric Counselling

Often not reported

Variant of Uncertain Significance

Novel/new CNV of unknown function

Involves genes of unknown function

May be parental as well in normal parent (susceptibility locus?)

Difficult interpretation: may

or may not be answer

Requires careful counselling/ and explanation for this and future

pregnancies

Normal – empiric counselling

More and more microdeletion/ duplication syndromes being discovered in ID/MCA

• Examples of clear-cut pathogenic chromosome syndromes:– VCFS/22q11 deletion– 4p- (Wolf Hirschorn)– Williams Syndrome– 5p- Cri Du Chat– 1p36 microdeletion– aneuploidies

• Improving literature, and prognostic/ outcome information available on these to help counsel families

• 2 useful websites:• Genereviews http

://www.ncbi.nlm.nih.gov/books/NBK1116/• Unique:

http://www.rarechromo.org/html/DisorderGuides.asp

https://decipher.sanger.ac.uk/disorders#syndromes/overview

6mo boy admitted for failure to thrive and developmental delay

• Dysmorphic features• Irritable• Very delayed• Poor weight gain

Father also had ID and similar dysmorphic features

Deletion on chromosome 1q21.1

• What does it mean???• What influence will this have on health and

outcomes

1q21.1 microdeletion syndrome

With international databases, literature and factsheets

• We can start to give families an idea of what to expect

• Can explain exactly what genes are involved and begin to understand pathogenicity of these deletions and duplications

Many of these are ‘susceptibility loci’ rather than clear cut syndromes

• Ie. Patients have increased ‘risk’ of developing problems– Structural/anatomical– Learning/behavioural– Epilepsy– Psychiatric problems

• But due to variable penetrance, cannot give absolute likelihood of these problems

• Makes prenatal counselling very tricky!

VOUS and Susceptibility Locus counselling is tricky

• Especially in setting of parental intellectual disability or subtle learning problems

• Usually a parent also carries it– Therefore 50% recurrence risk– May be subtle ID/abnormalities– This may or may not be reassuring for families

• ‘So he’ll just be like dad’

• ‘He could be even worse than mum’• Nonpenetrance and variability is high, and difficult concepts to grasp• Beware multiple VOUSes esp. in families with lots of ID! These found

to have compounding effect in literature.• Difficult decision-making in prenatal and pregnancy planning stages• CONSENT and pre-warning families is essential!

• 17yo• Microcephaly, Dev delay, dysmorphic, difficult behaviour• CMA performed

• 3p25.3 deletion

VHL haploinsufficiency

• Haemangioblastoma of brain, spinal cord, retina• Renal clear cell carcinoma• Phaeochromocytoma• Need screening• Referred to cancer geneticist• Found to have haemangioblastoma!

Term baby with IUGR, microcephaly, periventricular calcification

• Any thoughts on diagnosis?• 1900gm, symmetrically small• MRI: calcification right caudothalamic groove

TORCH, urine, showed CMV, IgM positive

• But someone ordered an array!• This revealed 2 deletion VOUSes…– 11q14.3 – 13q12.3

11q14.3 VOUS, 12 genes, unknown function…

What’s going on here?

What’s going on here?

Issues raised

1. Consent – were the family warned something like this could come up?2. Role/duty of care – neonatal/genetics unit in dealing with family with adult-onset disorder/risk3. Detailed genomic testing shouldn’t be ordered in patients when not indicated 4. We all carry VOUSes and benign CNVs…

These are the 4 possible outcomes of every array, which need to be discussed in the consent

Array for prenatal abnormality (with

consent)

Pathogenic CNV – likely answer

Clearly defined microdel/dup

syndrome

Based on size and location

Counsel +/- genetics involvement, especially for

recurrence information

Consider parentals (unlikely if severe)

Benign CNV – Unlikely answer

Based on literature/ population CNV

databases

Maybe also found in a normal parent

Unlikely answer – Empiric Counselling

Often not reported

Variant of Uncertain Significance

Novel/new CNV of unknown function

Involves genes of unknown function

May be parental as well in normal parent (susceptibility locus?)

Difficult interpretation: may

or may not be answer

Requires careful counselling/ and explanation for this and future

pregnancies

Normal – empiric counselling

Future directions…• Pickup CMA still very low!• Next-generation sequencing in prenatal setting is the next step…

– Eg. ‘exome’ or whole genome sequencing• Exome = just coding exons, 1-2% of genome, 50Mb, containing 85% of mutations

known to cause genetic disorders• Whole genome = all 3 billion bases of human genome

• Turnaround time, cost, and interpretation still difficult– Currently $1000/genome, 100Gb data, nobody to interpret…

• Theoretically improve diagnostic rate to 25-50%!• Difficulties of arrays exponentially increased! More VOUSes, ethical

dilemmas, interpretation, bioinformatics, counsellin• Based on trajectory of arrays, it’s only a matter of time…

Any Questions?• http://genome.ucsc.edu/• https://decipher.sanger.ac.uk/index• http://

www.genetics.edu.au/Publications-and-Resources/Genetics-Fact-Sheets/FactSheet6A

• Genereviews http://www.ncbi.nlm.nih.gov/books/NBK1116/

• Unique: http://www.rarechromo.org/html/DisorderGuides.asp

• www.omim.org