The prevalence of chromosomal deletions relating to developmental delay and/or intellectual disability in human euploid blastocysts

Abstract

Chromosomal anomalies in human embryos produced by in vitro fertilization are very common, which include numerical (aneuploidy) and structural (deletion, duplication or others) anomalies. Our previous study indicated that chromosomal deletion(s) is the most common structural anomaly accounting for approximately 8% of euploid blastocysts. It is still unknown if these deletions in human euploid blastocysts have clinical significance. In this study, we analyzed 15 previously diagnosed euploid blastocysts that had chromosomal deletion(s) using Agilent oligonucleotide DNA microarray platform and localized the gene location in each deletion. Then, we used OMIM gene map and phenotype database to investigate if these deletions are related with some important genes that cause genetic diseases, especially developmental delay or intellectual disability. As results, we found that the detectable chromosomal deletion size with Agilent microarray is above 2.38 Mb, while the deletions observed in human blastocysts are between 11.6 to 103 Mb. With OMIM gene map and phenotype database information, we found that deletions can result in loss of 81-464 genes. Out of these genes, 34-149 genes are related with known genetic problems. Furthermore, we found that 5 out of 15 samples lost genes in the deleted region, which were related to developmental delay and/or intellectual disability. In conclusion, our data indicates that all human euploid blastocysts with chromosomal deletion(s) are abnormal and transfer of these embryos may cause birth defects and/or developmental and intellectual disabilities. Therefore, the embryos with chromosomal deletion revealed by DNA microarray should not be transferred to the patients, or further gene map and/or phenotype seeking is necessary before making a final decision.

Figure 1. PGS charts of human blastocyst biopsies from Agilent oligo and Illumina BAC DNA array platforms.

Charts in left column are from Agilent and charts in right column are from Illumina BAC platforms. A and A': 46 XX; B and B': 46 XY; C and C': 47 XY, +14; D and D': 45 XY, −4, +15, -19. Arrows indicate chromosomal errors. Data matched between two array platforms.

Figure 2. PGS charts of human blastocyst biopsies from Agilent and NimbleGen oligo DNA array platforms.

Charts in A and D are from Agilent and charts in B, C, E and F are from NimbleGen platforms. A, B and C: 46 XY; D, E and F: 45 XX, -15. Arrow indicates chromosomal error. Data matched between two array platforms.

Figure 3. PGS chart and chromosomal view of a human blastocyst biopsy analyzed with Agilent array platform.

The PGS chart shows two chromosomal deletions (arrow) in chromosomes 5 and 12. The middle and bottom charts show the chromosomal views in both chromosomes, with deletion locations and sizes.

Figure 4. PGS chart, chromosomal view, gene view and gene list of a human blastocyst biopsy analyzed with Agilent array platform.

The PGS chart (A) shows one chromosomal deletion (arrow) in chromosome 13. Chromosomal view chart (B) shows the deletion location (13q21–13q33). Gene view chart (C) shows the location of genes (58,205,958–114,797,160) and D shows the list of lost genes in the deleted region. Genes marked with red are those related with phenotypes.