Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes
Abstract
:1. Introduction
2. Results
2.1. Pipeline from Raw Data to Molecular Genetic Diagnosis, PGx Report, and Medication Safety Card (MSC)
2.2. Evaluation of PGx Variants in gnomAD and Our In-House Cohort
2.3. Comparison of CYP2D6 Calling Tools from WGS Data
3. Discussion
4. Materials and Methods
4.1. PGx Profiling from WGS Data as well as Comparison of WGS and WES for PGx Profiling
4.2. Analysis of Star Alleles and Loss-of-Function Variants in gnomAD and in Our In-House WGS Cohort
4.3. Evaluation of CYP2D6 Variant Callers
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cohort | gnomAD Exomes v2.1.1 | gnomAD Genomes v3 | In-House WGS Cohort | |||
---|---|---|---|---|---|---|
Cohort Size | 125’748 Exomes | 71’702 Genomes | 547 Genomes | |||
Novel LOF/missense variants (not in ClinVar/HGMD/PharmGKB) 1 | n | % | n | % | n | % |
Total variants (alleles) | 823 (4′214) | 100.0 | 512 (6′940) | 100.0 | 10 (10) | 100.0 |
MAF > 5% | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
0.1% < MAF < 5% | 2 | 0.2 | 8 | 1.6 | 0 | 0.0 |
MAF < 0.1% | 821 | 99.8 | 504 | 98.4 | 10 | 100.0 |
Known LOF/missense variants (in ClinVar/HGMD/PharmGKB) 1 | n | % | n | % | n | % |
Total variants (alleles) | 103 (5′584) | 100.0 | 80 (2′706) | 100.0 | 4 (17) | 100.0 |
MAF > 5% | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
0.1% < MAF < 5% | 5 | 4.9 | 3 | 3.7 | 1 | 25.0 |
MAF < 0.1% | 98 | 95.1 | 77 | 96.3 | 3 | 75.0 |
DPWG variants | n | % | n | % | n | % |
Total variants (alleles) | 40 (375′331) | 100.0 | 45 (487′758) | 100.0 | 37 (4′162) | 100.0 |
MAF > 5% | 10 | 25.0 | 14 | 31.1 | 14 | 37.8 |
0.1% < MAF < 5% | 22 | 55.0 | 23 | 51.1 | 18 | 48.7 |
MAF < 0.1% | 8 | 20.0 | 8 | 17.8 | 5 | 13.5 |
Reference Samples | GeT-RM Consensus Genotype 2019 | Astrolabe v0.8.6.1 | Aldy v2.2.3 | Stargazer 1 v1.0.7 |
---|---|---|---|---|
HG00436 | *2×2/*71 | *2/*71 | *2×2/*71 | *1/*83+*2 |
NA07029 | *1/*35 | *1/*35 | *1/*35 | *1/*35 |
NA18959 | *2/*36+*10 | *2/*10 | *2/*36+*10 | *2/*36+*10 |
NA19109 | *2×2/*29 | *2/*29 | *2×2/*29 | *29/*83+*2 |
NA21781 | *2×2/*68+*4 | *2/*4 2 | *2×2/*68+*4 | *4N+*4/*68+*4 |
NA12878 in-house | *3/(*68)+*4 | *3/*4 3 | *3/*68+*4 | *3/*4 |
NA12873 | *1/*5 | *1/*5 | *5/*61 4 | *1/*5 |
NA18861 | *5/*29 | *5/*29 | *5/*29 | *13C/*29 |
HG00589 | *1/*21 | *1/*2 | *1/*21 | *1/*2 |
NA19917 | *1/*40 | *1/*40 | *1/*40 | *1/*40 |
NA07019 | *1/*4 | *1/*4 | *1/*4 | *1/*4 |
NA12717 | *1/*1 | *1/*1 | *1/*1 | *1/*1 |
HG00276 | *4/*5 | *4/*4 | *4/*5 | *4/*5 |
NA18524 | *1/*36×2+*10 | *1/*10 | *1+*36/*36+*10 5 | *1/*10×3 |
NA18540 | (*36+)*10/*41 | *41/*10 3 | *36+10/*61+*69 | *10×2/*41×2 |
NA12892 | *2/*3 | *2/*3 | *2/*3 | *2/*3 |
NA07348 | *1/*6 | *1/*6 | *1/*6 | *1/*6 |
NA18519 | *1/*29 6 | *1/*29 | *106/*29 | *106/*29 |
NA18966 | *1/*2 | *1/*2 | *1/*2 | *1/*2 |
NA18992 | *1/*5 | *1/*5 | *1/*5 | *1/*13C |
NA19226 | *2/*2×2 | *2/*2 2 | *2/*2×2 | *2/*83+*2 |
Total true | 12 | 19 | 11 | |
Total false | 9 | 2 | 10 |
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Caspar, S.M.; Schneider, T.; Meienberg, J.; Matyas, G. Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes. Int. J. Mol. Sci. 2020, 21, 2308. https://doi.org/10.3390/ijms21072308
Caspar SM, Schneider T, Meienberg J, Matyas G. Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes. International Journal of Molecular Sciences. 2020; 21(7):2308. https://doi.org/10.3390/ijms21072308
Chicago/Turabian StyleCaspar, Sylvan M., Timo Schneider, Janine Meienberg, and Gabor Matyas. 2020. "Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes" International Journal of Molecular Sciences 21, no. 7: 2308. https://doi.org/10.3390/ijms21072308