Flexible gene panels are essential for personalised genetic testing

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1 Flexible gene panels are essential for personalised genetic testing Stephen Abbs East Anglian Medical Genetics Service Cambridge University Hospitals NHS Foundation Trust

2 Clinical exome sequencing GEMINI clinical exome sequencing Introduced for routine testing, Feb 2014 Over 2600 diagnostic tests performed

3 Ability to test for large number of conditions - patient equity Flexible and responsive to clinical referrals Tests are visible and accessible Affordable High quality Requirements and advantages of clinical exome sequencing

4 GEMINI - CE Genomic Medicine Innovative Initiative Clinical Exome Illumina TruSight One sequencing panel Targets 4,813 clinically relevant genes NextSeq (36) / MiSeq (3) Coming September - TruSight One Expanded 1924 new genes Improvements to poorly performing regions

5 Diagnostic request Gene(s) sequenced and cost effective? Yes No Virtual gene panel(s) selected or established with referring/local consultants Alternative tests Clinical exome sequenced Data filtered for variants in virtual panel(s) Interpret variants, confirm pathogenic mutations Report

6 Number of virtual gene panels

7 Flexible gene/panel selection Referrals have been analysed for: Single gene panel (261 panels established) Single gene (88 genes) Multiple panels (2-8 panels; mean 2.5) Multiple genes (2-7 genes; mean 1.7) Panel(s) + gene(s) (1-12 panels; mean 1.7; 1-10 genes; mean 1.8)

8 Gene/panel selection 2663 referrals multiple panels 10.1% multiple genes 1.7% panel(s) + gene(s) 3.2% single gene 3.3% single panel 81.7%

9 Gene/panel selection 2663 referrals Combination of panels / genes 15%

10 Now 21% of referrals are for combinations of panels/genes % of referrals N=1091 N= N=

11 Example cases demonstrating flexibility of exomes

12 Example 1 9 year old with congenital ataxia and developmental delay Maternally inherited 918 kb heterozygous del 8q12.1 Carbonic anhydrase VIII, CA8 gene in deleted region - rare autosomal condition Cerebellar ataxia, mental retardation and disequilibrium syndrome 3, CAMRQ3 CA8: c.182a>g p.(try61cys) hemizygous variant, likely pathogenic

13 Example 2 2 year old with complex phenotype. Tested initially for septo-optic dysplasia (PAX6, HESX1). Mother met mother of a child with genitopatellar syndrome via SWAN, KAT6B mutation detected by DDD. Thought both children had same condition. Re-analysis of data detected de novo heterozygous likely pathogenic variant KAT6B: c.3893_3894insa p.(thr1300asnfs)

14 Example 3 6 month old with infantile spasms, microcephaly, lissencephaly, oculomotor apraxia, developmental delay. initially tested for epileptic encephalopathy panels. MRI result indicated further testing DCX, ACTB, ACTG1, DYNC1H1, RELN, TUBA1A, VLDLR, (KIF2A, TUBG1). Re-analysis of data detected heterozygous likely pathogenic variant TUBA1A: c.1186g>a p.(asp396thr). Consistent with phenotype

15 Flexibility of exomes Non-standard patient pathways eg 1. genes within deleted region 2. new phenotypic indications 3. new diagnostic test results Complex / heterogeneous clinical presentations requiring bespoke combination of tests

16 Improving access to genetic tests via exome sequencing Concept of exome sequencing is complex; referrals changed as clinicians gained experience Requirements: Readily accessible, up to date information about available tests Details of genes, panels, and approach to exome sequencing

17 clinical genetic test ordering platform established Doctors Online platform for ordering reliable tests from accredited labs Laboratories Searchable test catalogue Designed for genomics and Next Generation Sequencing Secure online payment Detailed quality metrics

18 Benefits of GeneAdviser platfom Tests readily found by gene, disease, laboratory Designed for displaying genomic sequencing panels Overlap between gene panels visible, useful for heterogeneous disorders Up to date information via API with lab s database Electronic ordering will reduce transcription between systems Simplified invoicing and payment Fast, secure delivery of reports to clinicians Just like Amazon!

Clinical exome sequencing Summary Ability to test for large number of conditions, ensuring patient equity Test requests have changed as clinicians become more familiar with exome testing

19 Clinical exome sequencing Summary Ability to test for large number of conditions, ensuring patient equity Test requests have changed as clinicians become more familiar with exome testing Flexible panel design is essential to allow appropriate testing for individual phenotypes (21% of referrals) - personalised medicine Genes and panels visible and readily accessible via GeneAdviser

Acknowledgements Laboratory: Howard Martin, Fay Rodger, Jaycen Parr, Gillian Flavell Bioinformatics: Kim Brugger, Matt Garner, Dilna Pushpajan Database: Ian Johnson Data analysis & reporting: Olivera

20 Acknowledgements Laboratory: Howard Martin, Fay Rodger, Jaycen Parr, Gillian Flavell Bioinformatics: Kim Brugger, Matt Garner, Dilna Pushpajan Database: Ian Johnson Data analysis & reporting: Olivera Spasic-Boskovic, Phil Twiss, Isabelle Delon, James Drummond, Ed Thompson, Namir Al-Hasso, Sarah Spiden, Julie Evans, Nick Gleadall, Sally Halsall, Harjeet Rai, Terence Elsey Patient referral: Numerous Clinical Geneticists around UK, Ruth Armstrong, Ramsay Bowden, Richard Sandford, Eamonn Maher et al GeneAdviser: Jelena Aleksic, Robert Stojnic

Rapid testing and prenatal diagnosis for at-risk couples presenting during pregnancy without a diagnosis

Rapid testing and prenatal diagnosis for at-risk couples presenting during pregnancy without a diagnosis Stephen Abbs East Anglian Medical Genetics Service Cambridge University Hospitals NHS Foundation