Unraveling the Diverse Landscape of Genomic Abnormalities from Conception to Childhood

Background: Genomic rearrangements are an important cause of genetic disease. A comprehensive overview of the nature and frequency of cytogenomic abnormalities adversely affecting human growth and development, from conception through childhood, has never been attempted.

Methods: We undertook a comprehensive, multi-year review of cytogenomic analysis of preimplantation genetic screening (PGS) of embryos (N=3349) and chromosomal microarray analysis (CMA) of pregnancy loss (N=8118), prenatal (N=3245), neonatal (N=1351) and pediatric (N=7047) samples. All samples were analyzed by CMA except for a subset of PGS samples (evaluated by next-generation sequencing).

Results: For embryo samples, 47% (1583/3349) demonstrated clinically significant chromosomal abnormalities (CSCAs), the majority of which (77%) were single or multiple whole chromosome aneuploidies (WCAs); interestingly, monosomies were 1.2 times more frequent than trisomies. For pregnancy loss, 54% (3975/7396) demonstrated WCAs or unbalanced structural abnormalities. The most common findings included trisomies (63%), triploidy (12%) and monosomy X (11%). For prenatal samples, 13% (418/3245) demonstrated CSCAs. Trisomies were most common (41%) followed by segmental deletions and/or duplications (45%). Of 1351 neonatal samples (0- ≤29 days) evaluated, 18% had CSCAs with WCAs being the most common (6%) and segmental abnormalities in 12%. For pediatric samples, CSCAs were present in 12% cases (854 of 7047), the majority of which were microdeletions (60%) or microduplications (23%).

Conclusions: The severity of the chromosomal abnormalities detected in embryos or early pregnancy loss reflect the incompatibility with successful implantation or progression to viable pregnancy. In contrast, the frequency of genomic alterations detected prenatally and neonatally correlates with the incidence of significant physical and developmental abnormalities, but not necessarily incompatible with life. The pediatric samples showed a preponderance of less drastic microdeletions/duplications, which resulted in both syndromic and non-syndromic phenotypic abnormalities. These data reveal an interesting evolution of genomic alterations of decreasing severity as human growth progresses from conception though childhood.