The Focused Exome service at Bristol Genetics Laboratory

Transcription

1 The Focused Exome service at Bristol Genetics Laboratory Chris Buxton Maggie Williams July 2016

2 Bristol Clinical exome Service to mid July Validation: Agilent FE kit, NextSeq 500 and new pipeline 1st reports Jan 2016 Casemix 52 defined 'active' panels 220 panels requested (1/3 are 56 cd vs. 2/3 112 cd TAT) 80 reported

3 New virtual panel acceptance criteria No large pre-populated list of panels New panel assessment + setup New request MDT Other clinical contact (CG vs non CG)? Existing UKGTN provider no Assess coverage okay Review disease mechanism mostly seq Discuss at weekly lab meeting yes poor e.g. commonly CNV depends depends

4 Phenotypic prioritisation Validation underway: Exomiser Workup / Validation plan Take 50 well phenotyped existing (custom) ngs panel patients.. with Class 4 / 5 results Merge their full custom panel genotype with clinical exome dataset:.. eg Coriell NA12878 Cell line Us these spiked dummy patients for validation Set significance thresholds / utility Other options Other prioritisation tools Variant filtering / mining vs disease databases e.g. HGMD pro Bone WP et al., Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency. Genet Med Jun;18(6):

5 Management tools: Challenges to address Performance of newly proposed panels Coverage assessment Bedfile creation Mechanism to manage new services: LIMS limitations Panel maintenance Caselists management Case allocation

6 Labhelper: Coverage checker Coverage assessment Rapid assessment of ad-hoc panels

7 Labhelper: Coverage checker

8 Labhelper: Coverage checker Sanger fill

9 FE Management tool: Case management Auto allocation to lists Scientist allocation HPO terms Variant recording Stage tracking Dynamic filtering

10 FE Management tool: Panel content Gene content Pipeline integration Version control Modular approach Single phenotype panels Combo phenotype panels

11 Different ways of working: Workflow Lots of different Scientists add to Pending list 24 samples added to plate on LIMS Lab processing (manual) Index info Virtual panel info Patient info NextSeq raw data to BI Subset virtual panel results for analysis Load into Geneticist Assistant (annotation & variant database) vcf bam Coverage metrics CNV Case distribute to named Scientist

12 Different ways of working cd TATs in one service Increased workload for service management Demand + streamlining Staffing levels, automation, lab capacity, informatics Technical: Panel Version control Synchronisation of virtual panel content between pipeline / downstream software. Reanalysis of normal result patients CNV: Limits of analysis?

13 CNV assessment: Limits of analysis Known CNV positives: 2x 16p13.1 dup TAAD risk factor (+ schizophrenia ) T21 patient Klinefelter patient: Sex-linked genes on panel / incidental findings? Newly ascertained: Interstitial dup 15q

14 Different ways of working. Change in referral / testing patterns Shift to test more in-house, multiple genes requested Variable local uptake Engagement with MDTs Phenotype vs genotype etc Direct quote from Consultant CG:..For us as clinicians when assessing children if there are several different conditions going through your head although no obvious definite diagnosis the clinical exome is great way of testing for these conditions and then having the option of further analysis if no clear answer. Provides a much more efficient and cost effective solution..

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