P-696 Identification of novel candidate genes associated with meitotic aneuploidy in human embryos by whole-exome sequencing (WES)
Authors: Lledo B , Marco A , Morales R , Ortiz J A , García-Hernández E , Lozano F , Cascales A , Guerrero J , Bernabeu A , Bernabeu R 
Published: June 2023

Study question

Can certain genetic variants in women cause a genetic predisposition to aneuploidy?

Summary answer

Our results suggest that the maternal variants identified in genes regulating meiotic processes could be useful genetic biomarkers for predicting a predisposition to embryonic aneuploidies.

What is known already

Errors in chromosome segregation during meiosis as chromosome synapsis, crossing-over and spindle building, occur frequently in human oocytes and cause aneuploidy in embryos. These errors increase dramatically in the oocytes of older women. However, the rate of producing aneuploidy oocytes varies among IVF patients for a given age. Recent publications have identified genetic variants that are crucial for producing healthy oocytes in female IVF patients. The association between maternal genetic variants and embryonic aneuploidy risk suggests the potential of using genomic data to predict embryonic aneuploidy risk. Our aim was to identify novel variants and candidate genes for embryonic aneuploidy.

Study design, size, duration

A prospective observational cohort study was done including 127 trophoectoderm biopsies from 29 couples who performed whole-exome sequencing (WES) and PGT-A between November 2019 and March 2022. Women were 35 years old or younger and normal karyotype for men and women. Patients were divided in two groups according to the embryo aneuploidy rate expected by their maternal age: ≤ 50% of aneuploid blastocysts as control group(n = 14), and ≥ 50% of aneuploid blastocysts as study group(n = 15).

Participants/materials, setting, methods

WES was performed using Trusight One Expanded Sequencing Panel (Illumina®). The following criteria were used for filtering and annotation of candidate variants: (1) minor allele frequency (MAF) &lt;0.05 in the gnomAD and 1000 genomes, (2) variants in genes previously associated with chromosome segregation, chromatin cohesion, meiosis and cell division processes, (3) exonic/splicing boundaries variants, (4) variants having potentially strong/moderate functional effects on the protein evaluated using three in silico prediction algorithms (SIFT, PolyPhen-2 and MutationTaster).

Main results and the role of chance

Overall, the mean female and male age was 26.21 + 4.11y and 40.69 + 9.07y respectively. No differences were shown between groups for patient characteristics. Regarding PGT-A cycle no differences were seen between the number of oocytes and MII retrieved. However, the mean number of biopsied embryos per patient (5.36 + 2.50 vs 3.47 + 1.36; p &lt; 0.05) as well as the percentage of embryos biopsied on day 5 (85.33 vs 32.69; p &lt; 0.05) were higher in the control group. Finally, as expected, the percentage of aneuploidies was higher in the study group (18.64 vs 71.89; p &lt; 0.05). 45 variants were identified in genes potentially associated to the mechanism related to the phenotype. After the variant filtering six probably pathogenic variants were identified. The variants found in the genes were: c.1397T&gt;C (TLE6), c.169G&gt;A (IKBKG), c.1227A&gt;C (BUB1B), c.277G&gt;A (TP73), c.190C&gt;T (PLXNA3) and c.744C&gt;G (AURKC). All variants were heterozygous and all of them were of maternal origin. The females carrying the candidate variants belonged to the study group, and two variants in different genes were identified in one patient. No potentially pathogenic variants were detected in patients from the control group. Therefore, the average detection rate of genetic variants with potential impact in embryo aneuploidy was 33.33% (5/15).

Limitations, reasons for caution

A notable strength of our study is the inclusion of both (male and female) genomic data. On the other hand, our study has certain limitations including the inherent challenges of any observational study, also, the pathogenicity of the identified variants should be validated in further functional studies.

Wider implications of the findings

We described new candidate genes that have never been associated to meiotic embryo aneuploidy and are involved in important biological processes (cell division and chromosome segregation). WES may be considered as an efficient tool to identify patients with higher risk of embryo aneuploidy allowing an individualized genetic counselling in advance.

Trial registration number

Not applicable