Challenges of CGH array testing in children with developmental delay. Dr Sally Davies 17 th September 2014

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1 Challenges of CGH array testing in children with developmental delay Dr Sally Davies 17 th September 2014

2 CGH array What is CGH array? Understanding the test Benefits Results to expect Consent issues Ethical and social implications Illustrative cases

3 Evidence The incidence of DD in the general population approaches 3% Array CGH offers a higher diagnostic yield (15-20%) in this patient population than a G-banded karyotype (5%) David T. Miller et al; The American Journal of Human Genetics 86, , May 14, 2010

4 Genomic variation Single nucleotide polymorphism (SNP) 100% - 3 million per genome 0.1% of variation non pathogenic Copy number variation (CNV) 1-5Kb in 100% of population 100 per genome 1% of variation some pathogenic Microscopically visible changes >5 Mb in 0.5% population Almost always pathogenic

5 Genetic Tests

6 SIGNATURE GENOMIC LABORATORIES, LLC

7 SIGNATURE GENOMIC LABORATORIES, LLC

8 Fluorescent labels (e.g. Cy5 and Cy3) Hybridize to microarray Scanner Analysis and interpretation Confirmation

9 Copy Number Variation Pathogenic - well-established syndromes, de novo variants, and large changes VUS - no associated disorder, however imbalance includes several genes and parental analysis is needed to aid in interpretation (likely pathogenic & likely benign) Benign - well described common polymorphism in normal individuals

10 karyogram Green = copy number gain Red = copy number loss Copy number changes Written report Data available for interpretation: DGV DECIPHER OMIM Laboratory history data ISCA Literature search PHENOTYPE

11 DECIPHER

12 PATHOGENIC known to be associated with a large imbalance(s) with clearly established clinical significance.

13 PATHOGENIC Imbalance known to be associated with specific disorder (targeted region) A 3.66 Mb deletion of the short arm of chromosome 17, maps to the Smith Magenis microdeletion syndrome. The imbalance is well documented as clinically significant in multiple peerreviewed publications and penetrance and expressivity is understood.

14 Uncertain Imbalance known to contain genes but not associated with any known condition A 2.3Mb duplication of the long arm of chromosome 22. The duplication maps to the distal end of the 22q11.2 duplication syndrome region. The clinical significance of this imbalance is unclear. UNCERTAIN SIGNIFICANCE includes findings that are later demonstrated to be clearly pathogenic or clearly benign..

15 LIMITATIONS Unable to detect polyploidy, low level mosaicism and balanced rearrangements Conventional G-band Analysis

16 Array CGH Testing Criteria One or more of the following: Learning disability Developmental delay Behavioural problems & autism Dysmorphic features Congenital anomaly

17 Benefits Detects chromosome imbalances at a greater resolution compared with karyotyping Simultaneously and rapidly evaluates thousands of regions of the genome Accurately identifies the type, number and location of the pathogenic genes involved in the chromosome imbalances Family members can be tested to see if they are carriers of changes in their DNA

18 Challenges Is a result pathogenic? Are family studies required? Inherited De novo Newer syndromes? What do I do next?

19 Challenges Is a result reliable pathogenic? Are family studies required? Inherited De novo Newer syndromes? What do I do next? Refer to genetics

20 Results to expect No answer Definite answer Uncertainty Unrelated finding

21 Consent Possible results Parental testing Family implications Something else Makes it easier when get a VUS

22

23 An abnormal male chromosome complement with a 13.2Mb terminal copy number loss of the long arm of chromosome 4, and a 12.7Mb terminal copy number gain of the long arm of chromosome 18.

24 Page not available Case

25 15q13.3 deletion Inherited

26 Page not available Case

27 Page not available Case

28 16p11.2 Deletion? inherited

29 Implications

30 Implications

31 Implications

32 Summary Fantastic tool Pathogenicity Variability Family studies Something else Significance for family members

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