In vitro screening of embryos by whole-genome sequencing: now, in the future or never?
OBJECTIVE
What are the analytical and clinical validity and the clinical utility of in vitro screening of embryos by whole-genome sequencing?


CONCLUSIONS
At present there are still many limitations in terms of analytical and clinical validity and utility and many ethical questions remain.


BACKGROUND
Whole-genome sequencing of IVF/ICSI embryos is technically possible. Many loss-of-function mutations exist in the general population without serious effects on the phenotype of the individual. Moreover, annotations of genes and the reference genome are still not 100% correct.


METHODS
We used publicly available samples from the 1000 Genomes project and Complete Genomics, together with 42 samples from in-house research samples of parents from trios to investigate the presence of loss-of-function mutations in healthy individuals.


METHODS
In the samples, we looked for mutations in genes that are associated with a selection of severe Mendelian disorders with a known molecular basis. We looked for mutations predicted to be damaging by PolyPhen and SIFT and for mutations annotated as disease causing in Human Genome Mutation Database (HGMD).


RESULTS
More than 40% of individuals who can be considered healthy have mutations that are predicted to be damaging in genes associated with severe Mendelian disorders or are annotated as disease causing.


CONCLUSIONS
The analysis relies on current knowledge and databases are continuously updated to reflect our increasing knowledge about the genome. In the process of our analysis several updates were already made.


CONCLUSIONS
At this moment it is not advisable to use whole-genome sequencing as a tool to set up health profiles to select embryos for transfer. We also raise some ethical questions that have to be addressed before this technology can be used for embryo selection.


BACKGROUND
N/A.
Department of Electrical Engineering (ESAT), STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics, KU Leuven, Leuven, Belgium.
Raf
R
Winand
Kristien
K
Hens
Wybo
W
Dondorp
Guido
G
de Wert
Yves
Y
Moreau
Joris Robert
JR
Vermeesch
Inge
I
Liebaers
Jan
J
Aerts
D001755:Blastocyst; D004252:DNA Mutational Analysis; D015894:Genome, Human; D006801:Humans; D019836:Preimplantation Diagnosis / Q000941:ethics / Q000379:methods* / Q000639:trends; D018570:Risk Assessment / Q000379:methods
PGD; PGS; embryo; ethics; whole-genome sequencing