Comprehensive carrier genetic test using next-generation deoxyribonucleic acid sequencing in infertile couples wishing to conceive through assisted reproductive technology.
OBJECTIVE
To develop an expanded pan-ethnic preconception carrier genetic screening test for use in assisted reproductive technology (ART) patients and donors.


METHODS
Retrospective analysis of results obtained from 2,570 analyses.


METHODS
Reproductive genetic laboratory.


METHODS
The 2,570 samples comprised 1,170 individuals from the gamete donor programs; 1,124 individuals corresponding to the partner of the patient receiving the donated gamete; and 276 individuals from 138 couples seeking ART using their own gametes.


METHODS
None.


METHODS
Next-generation sequencing of 549 recessive and X-linked genes involved in severe childhood phenotypes reinforced with five complementary tests covering high prevalent mutations not detected by next-generation sequencing.


RESULTS
Preclinical validation included 48 DNA samples carrying known mutations for 27 genes, resulting in a sensitivity of 99%. In the clinical dataset, 2,161 samples (84%) tested positive, with an average carrier burden of 2.3 per sample. Five percent of the couples using their own gametes were found to have pathogenic variants conferring high risk for six different diseases. These high-risk couples and patients received genetic counseling and recommendations for preimplantation genetic diagnosis. For patients receiving gamete donation, we applied a genetic testing and blinded matching system to avoid high-risk combinations regardless of their carrier burden. For female donors, 1.94% were positive for X-linked conditions; they received genetic counselling and were discarded.


CONCLUSIONS
We have developed a comprehensive carrier genetic screening test that, combined with our matching system and genetic counseling, constitutes a powerful tool to avoid more than 600 mendelian diseases in the offspring of patients undergoing ART.
IGenomix, Parc Cientific Univeristat Valencia, Valencia, Spain. Electronic address: julio.martin@igenomix.com.
Julio
J
Martin
Binhai Genomics Institute and Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin, People's Republic of China.
Asan
Binhai Genomics Institute and Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin, People's Republic of China.
Yuting
Y
Yi
IGenomix, Parc Cientific Univeristat Valencia, Valencia, Spain.
Trinidad
T
Alberola
IGenomix, Parc Cientific Univeristat Valencia, Valencia, Spain.
Beatriz
B
Rodríguez-Iglesias
IGenomix, Parc Cientific Univeristat Valencia, Valencia, Spain.
Jorge
J
Jiménez-Almazán
BGI-Shenzen, Shenzhen, People's Republic of China.
Qin
Q
Li
Binhai Genomics Institute and Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin, People's Republic of China.
Huiqian
H
Du
Instituto Valenciano de Infertilidad Valencia and Fundación Instituto Valenciano de Infertilidad, Valencia, Spain.
Pilar
P
Alama
Instituto Valenciano de Infertilidad Valencia and Fundación Instituto Valenciano de Infertilidad, Valencia, Spain.
Amparo
A
Ruiz
Instituto Valenciano de Infertilidad Valencia and Fundación Instituto Valenciano de Infertilidad, Valencia, Spain.
Ernesto
E
Bosch
BGI-Shenzen, Shenzhen, People's Republic of China.
Nicolas
N
Garrido
IGenomix, Parc Cientific Univeristat Valencia, Valencia, Spain; Instituto Valenciano de Infertilidad Valencia and Fundación Instituto Valenciano de Infertilidad, Valencia, Spain; Department of Obstetrics and Gynecology, Valencia University, Instituto Universitario IVI/INCLIVA, Valencia, Spain.
Carlos
C
Simon
D004252:DNA Mutational Analysis; D005260:Female; D006580:Genetic Carrier Screening / Q000379:methods*; D005817:Genetic Counseling; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007246:Infertility / Q000175:diagnosis / Q000235:genetics / Q000628:therapy*; D008297:Male; D009154:Mutation; D010641:Phenotype; D016742:Preconception Care / Q000379:methods*; D011237:Predictive Value of Tests; D019836:Preimplantation Diagnosis; D015203:Reproducibility of Results; D027724:Reproductive Techniques, Assisted; D012189:Retrospective Studies; D012307:Risk Factors
Assisted reproductive technology; carrier; genetic screening; infertility; next-generation sequencing