1. 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

2. 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

3. 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

4. Publications
Parks et al, 2016
Parks et al,
2017

5. 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)

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

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

8. Referral centres

10. 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

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

12. Fetal fraction
2.40% %
Mean: 7.88%

13. 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%)

14. 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

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

16. 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

17. 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:
Dr Elizabeth Young:
Benjamin Bowns:
Health Innovation Challenge Fund
Patients, donors and national collaborators involved in recruitment