Implementation of the DDD/ClinGen OGT (CytoSure v3) Microarray

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1 Implementation of the DDD/ClinGen OGT (CytoSure v3) Microarray OGT UGM Birmingham 08/09/2016 Dom McMullan Birmingham Women's NHS Trust

2 WM chromosomal microarray (CMA) testing Population of ~6 million (10%) Chromosomal microarray (CMA) First-line test for all DD patients >5,000 per annum plus 15% growth Prenatal diagnosis (structural anomalies) Fetal pathology

3 Typical DD Pathway until 2015 CMA +/- single gene testing Deciphering Developmental Disorders (DDD) 12,000 trio exomes +/- ultra-high res arraycgh

4 Typical DD Pathway from 2016? CMA Clinical Exome (filtered) 100,000 whole genomes

5 Balancing factors for platform choice in Clinical Genomics Cost Detection rate Ease of analysis Throughput Discovery less important?

6 CMA platform choices Lowest cost, highest detection rate Available platforms within UK cost envelope: OGT / Agilent based 8x60k design (acgh) Affymetrix CytoScan 750k (SNP+CN based) Illumina CytoSNP 8x850k (SNP based)

7 DDD project Transformed Clinical Genetics in UK DECIPHER 12,000 exomes back to NHS Ended diagnostic odyssey Discovered >12 new genes Expedited interpretation skills the Genomic MDT DDG2P evidence based gene list

8 Evidence Bases for new OGT (v3.0) DDD array DDG2P gene list (n=>1,400) Disorder, Mechanism, Consequence and HI scores ISCA/ClinGen dosage sensitivity map ISCA/ClinVar submitted clinical cases DECIPHER recurrent syndromes OGT v3.0 60k CNV, 180k CNV and 180k CNV+SNP designs

9 DDG2P centric gene targeting ~300 Monoallelic / LoF genes at single exon resolution ~200 Monoallelic missense /uncertain genes at gene level Additional coverage in DECIPHER curated syndrome regions Evidence based backbone (ISCA/ClinGen pathogenic + HI score) Tier 1; ~120kb HI gene rich / reported pathogenic CNVs Tier 2; ~300kb Tier 3; ~500kb agenic / no reported pathogenic CNVs Theoretical resolution based on 3-probe calling

10 Validation Bank of 1,000s of known abnormal cases CNVs at limits of detection previously E.g. 2 probe calls Mosaics Many samples have data for: BlueGnome / Illumina 60K ISCA v2.0 Affymetrix CytoScan-HD and 750K SNP array Illumina CytoSNP SNP bead array 850K CHALLENGING CASES

11 DLR spread comparison; 48 sample validation Mean DLR: OGT v3 DDD = 0.115, Illumina v2 = 0.158

12 Deletion at 1q41-q42 8.7Mb deletion; mean log2 ratio, -0.9 Highly consistent probe behaviour; all 119 probes < -0.6

13 PDHA1 deletion (Xp22.2) 35 probes on v3 array Multi-exon 13kb deletion

14 MEF2C deletion (5q13.4) Manually called and validated from ISCA v2.0 array (2 probes only) 36 probes called on v3 array Minimum size 68kb; multiple exons

15 CREBBP (Rubenstein-Taybi) deletion (16p22.2) Manually called and validated from ISCA v2.0 array (2 probes only) 9 probes called on v3 array Minimum size 2.2kb; 2 exons

16 MID1 (Opitz-G) intragenic duplication (single exon) Previous detection by 2x105k OGT X-array 4 probes called on DDD array Minimum size 500bp (single exon)

17 MID1 (Opitz-G) intragenic duplication (single exon) Previous detection by 2x105k OGT X-array 4 probes called on v3 array Minimum size 500bp (single exon)

18 Investigations 46 XY 22q- FISH: NAD (brothers) Opitz-G? MID1 seq ( Naples 2006): NAD 1Mb BAC array: NAD X/Y tiling BAC array: NAD OGT X exon array; intragenic dup DDD acgh: NAD DDD exome: intragenic dup

19 TBX5 12q24 deletion (Holt-Oram) Minimum 450bp 3 probes, 1 exon

20 Mosaic trisomy 18? Low level mosaic on peripheral blood in IUGR neonate Confirmation on buccal swab

21 Mosaic trisomy 18? Aneuploidy summary plot Low level mosaic on peripheral blood in IUGR neonate Confirmation on buccal swab

22 Validation of CNVs from DDD

23 Validation of CNVs from DDD 12,000 undiagnosed UK trios recruited Majority had routine acgh in local centres WES and ultra-high resolution acgh at Wellcome Trust Sanger Institute, Cambridge Plausible pathogenic data fed-back to local clinical/laboratory teams for validation 1200 trios from WM region 300 variants so far (SNVs and CNVs)

24 DDD Research Report

25

26 Array-CGH (2x1m Agilent custom) De novo 1.27kb deletion

27 HDAC8 deletion confirmation 1.17kb deletion (minimum) 2 exons, 7 probes

28 HDAC8 deletion confirmation 1.17kb deletion (minimum) 2 exons, 7 probes

29 Predictive comparison in UCSC Platform Min Max OGT /DDD v3.0 Illumina 850k CytoScan HD

30

31 DDD validation Case 2: History Intellectual disability (severe) Autistic Self-mutilation Ptosis

32 DDD Research Report

33

34 De novo 3.8kb Array-CGH (2x1m Agilent custom) De novo 3.8kb deletion

35 MED13L deletion confirmation 269bp deletion (minimum) 1 exon (9), 3 probes

36 MED13L deletion confirmation 269bp deletion (minimum) 1 exon(9), 3 probes

37 MED13L deletion confirmation 269bp deletion (minimum) 1 exon(9), 3 probes

38 Predictive comparison in UCSC Platform Min Max OGT /DDD v3.0 Illumina 850k CytoScan HD

39

40 DDD validations Genotype-phenotype discussion in local MDT Both de novo cases fit clinical phenotypes Clinical reports issued Rapid, cost-effective validations Answers would have been possible for families years previously via acgh if DDD array had been available..

41 Prospective exonic CNV diagnoses (OGT/DDD array implemented April 2016)

42 Single exon deletion (1.2kb); ARSE Dysmorphic Skeletal anomalies Parental samples requested Chrondrodysplasia Punctata (X-linked)

43 Single exon deletion (1.2kb); ARSE

44 Single exon (1kb) PTPN11 dysmorphic?vsd/asd puffy hands/feet short 5th fingers Parental samples requested

45 Single exon (1kb) PTPN11 dysmorphic?vsd/asd puffy hands/feet short 5th fingers Parental samples requested

46 Single exon (1kb) PTPN11

47 PTPN11; DECIPHER

48 Single exon (1.1kb) GRIN2A ILD Motor delay DE NOVO

49 Balancing factors Exonic deletions SNPs: AOH/UPD

50 Application of v3 4x180K SNP array Unusual case of autosomal recessive Bartter syndrome Clinician; Homozygous deletion via UPD event? Bartter syndrome type 4B Renal salt wasting Deafness CLCNKA and CLCNKB Bartter syndrome type 3 Renal salt wasting CLCNKB

51 Chr1 (whole chromosome)

52 Chr1 (whole chromosome) Regions of UPD (AOH)

53 Homozygous deletion in region of UPD 1p36.13

54 Homozygous deletion in region of UPD 1p36.13 Algorithmic deletion call Deleted probes only mapped to CLCNKB; NO probes in CLCNKA

55

56 OGT/DDD v3 180k SNP Beta test data

57 OGT/DDD v3 180k SNP Beta test data CLCNKA not deleted No deafness Bartter Type 3

58 Summary OGT/DDD 8x60k implemented all referrals Single exon deletions can be detected if targeted Will detection rate increase? 3/400 (0.75%) WM DDD cases have pathogenic single exon changes >7/1500 (>0.5%) prospective cases missed previously? How much has been missed? High density does not equate to high resolution New genes = future versions? BUT have the majority of haploinsufficient genes now been discovered? Prevalence and architecture of dominant developmental disorders

59 Summary Extended life for chromosomal microarray? Rapid, cost-effective detection of recurrent CNV syndromes Exome/panel CNV calling improvements? CNV calling in WGS / 100kgp data? Need for higher resolution data-sets ExAC CNV data released August 2016 Clinical CNV data

60 Data-sharing NHS Data-sharing consortium (semi) auto-upload capability to DECIPHER OGT software export plug-in Auto-upload via API functionality being explored SNV and CNV worlds are colliding Interpretation requires all variattion THIS DATA NEEDS SHARING

61 NHS Data-sharing Consortium

62 Data Collection How common are smaller exonic changes? e.g <3 exons What has been missed? Unusual mechanisms/ genotype-phenotype? This UGM as a forum to drive data-collection project OGT keen to support collaborative study DDD team keen to collaborate on joint publication

63 Acknowledgements WMRGL team Rowena Roberts Lisa Reali, Sam Martin, Dave Bohanna, Laura Scott, Gareth Masson, Fiona Togneri DDD / DECIPHER team OGT team Thank-you for your attention!!

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