1. Can view other patients

2. Also search Pubmed, google, etc

3. 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’

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

5. A good factsheet for consent http://www.genetics.edu.au/Publications-and-Resources/Genetics- Fact-Sheets/FactSheet6A

6. 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

7. 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

8. 2 useful websites: Genereviews http://www.ncbi.nlm.nih.gov/books/NBK1116/ttp://www.ncbi.nlm.nih.gov/books/NBK1116/ Unique: http://www.rarechromo.org/html/DisorderGuides.asp http://www.rarechromo.org/html/DisorderGuides.asp

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

10. 6mo boy admitted for failure to thrive and developmental delay Dysmorphic features Irritable Very delayed Poor weight gain

11. Father also had ID and similar dysmorphic features

12. Deletion on chromosome 1q21.1 What does it mean??? What influence will this have on health and outcomes

13. 1q21.1 microdeletion syndrome

15. 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

16. 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!

17. 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!

18. 17yo Microcephaly, Dev delay, dysmorphic, difficult behaviour CMA performed

19. 3p25.3 deletion

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

21. Term baby with IUGR, microcephaly, periventricular calcification Any thoughts on diagnosis? 1900gm, symmetrically small MRI: calcification right caudothalamic groove

22. TORCH, urine, showed CMV, IgM positive But someone ordered an array! This revealed 2 deletion VOUSes… – 11q14.3 – 13q12.3

23. 11q14.3 VOUS, 12 genes, unknown function…

24. What’s going on here?

26. 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/risk 3. Detailed genomic testing shouldn’t be ordered in patients when not indicated 4. We all carry VOUSes and benign CNVs…

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

28. 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

29. 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…

30. Any Questions? http://genome.ucsc.edu/ https://decipher.sanger.ac.uk/index http://www.genetics.edu.au/Publications- and-Resources/Genetics-Fact- Sheets/FactSheet6A http://www.genetics.edu.au/Publications- and-Resources/Genetics-Fact- Sheets/FactSheet6A Genereviews http://www.ncbi.nlm.nih.gov/books/NBK11 16/ttp://www.ncbi.nlm.nih.gov/books/NBK11 16/ Unique: http://www.rarechromo.org/html/Disorder Guides.asp http://www.rarechromo.org/html/Disorder Guides.asp www.omim.org