West Midlands Regional Genetics Laboratory

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Presentation transcript:

West Midlands Regional Genetics Laboratory Non-invasive prenatal diagnosis (NIPD) of single gene disorders (SGDs) by relative haplotype dosage (RHDO): review of 18 months of clinical service Ben Bowns Clinical Scientist West Midlands Regional Genetics Laboratory

Background Non-Invasive Prenatal Diagnosis: Diagnostic – does not require confirmation Bespoke NIPD Amplicon based assays Paternal or de novo variants Rare disorders/private mutations Relative haplotype dosage (RHDO) Linkage-type assay Genotyping of 1000’s of targeted SNPs across disease gene region DMD/BMD, SMA, CF, CAH

RHDO linkage Advantages Limitations Detect maternal and paternal inheritance Suitable family structure required Not limited by type of variant De novo mutation No workup required Consanguinity

Publications Parks et al, 2016 Parks et al, 2017

Clinical service Sept 2016: RHDO for DMD/BMD & SMA Dec 2017: RHDO for CF Current capacity: 6 prenatal diagnoses per week (2 MiSeq runs) Target TaT 14 days Cost £1200 (NHS)

Test requirements 8+ weeks gestation Singleton pregnancies Non-consanguineous Prior knowledge of parental carrier status Samples required DNA from parents and affected/ unaffected

Sample numbers Total cases: 69 42 SMA,17 DMD/BMD,10 CF 2016: 7 2017: 32 2018: 36

Referral centres

Results Conclusive result in 63/69 pregnancies tested Disorder Unaffected Carrier Affected DMD/BMD 10 - 5 SMA 21 8 CF 1 3 Total 26 16 Conclusive result in 63/69 pregnancies tested

Results Turnaround Mean 11 days Gestation Range 7+5 – 15+ Mean 9+5 36 at <10 weeks CVS

Fetal fraction 2.40% - 16.88% Mean: 7.88%

Failure rate 4/67 (6%) Causes Undisclosed consanguinity (2) Persistent low fetal fraction (1) Insufficient maternal informative SNPs (1) Recombination close to mutation (2) Failure rate (invasive test required) 4/67 (6%)

Confirmed RHDO results RHDO clinical reports include request for follow-up information (post-pregnancy result) 24 received, all concordant with NIPD result 75 confirmed results 100% concordance

Conclusions NIPD by RHDO successfully implemented 69 prenatal diagnoses (UK and international) Early gestation testing Quick turnaround Low failure rate High accuracy

Future Planning Increase capacity – NextSeq Additional disorders by RHDO (agreed panel) Centralised delivery of testing Complemented by bespoke assay and individual panels where appropriate Availability for consanguineous couple Testing without a proband

Acknowledgements Health Innovation Challenge Fund NIPSIGEN team: Dr Michael Parks Dr Elizabeth Young Samantha Court Dr Amy Gerrish Dr Chipo Mashayamombe Julie Hewitt Siobhan Cleary Dr Samuel Clokie Dr Denise Williams Dr Trevor Cole Dr Fiona MacDonald Prof Mike Griffiths Dr Stephanie Allen Contact details Dr Stephanie Allen: Stephanie.Allen@bwnft.nhs.uk Dr Elizabeth Young: Elizabeth.Young@bwnft.nhs.uk Benjamin Bowns: Benjamin.Bowns@bwnft.nhs.uk Health Innovation Challenge Fund Patients, donors and national collaborators involved in recruitment