Abstract
Balanced chromosomal abnormalities (BCAs) are changes in the localization or orientation of a chromosomal segment without visible gain or loss of genetic material. BCAs occur at a frequency of 1 in 500 newborns and are associated with an increased risk of multiple congenital anomalies and/or neurodevelopmental disorders, especially if it is a de novo mutation. In this pilot project, we used short read genome sequencing (GS) to retrospectively re-sequence ten prenatal subjects with de novo BCAs and compared the performance of GS with the original karyotyping. GS characterized all BCAs found by conventional karyotyping with the added benefit of precise sub-band delineation. By identifying BCA breakpoints at the nucleotide level using GS, we found disruption of OMIM genes in three cases and identified cryptic gain/loss at the breakpoints in two cases. Of these five cases, four cases reached a definitive genetic diagnosis while the other one case had a BCA interpreted as unknown clinical significance. The additional information gained from GS can change the interpretation of the BCAs and has the potential to improve the genetic counseling and perinatal management by providing a more specific genetic diagnosis. This demonstrates the added clinical utility of using GS for the diagnosis of BCAs.
Highlights
Balanced chromosomal abnormalities (BCAs) are changes in either localization or orientation of a chromosomal segment without visible gain or loss of chromosomal material
We evaluated the genes disrupted at the translocation breakpoints, genes involved in cryptic deletion or duplication (i.e., copy number variants (CNV) not detectable by karyotyping), and alteration of topologically associated domains (TADs)
The findings from this study demonstrated the advantages of genome sequencing (GS) over conventional karyotyping on the detection of BCAs
Summary
Balanced chromosomal abnormalities (BCAs) are changes in either localization or orientation of a chromosomal segment without visible gain or loss of chromosomal material. Such abnormalities can be chromosomal rearrangements, such as translocations, inversions, insertions/excisions, or complex chromosomal rearrangements which are variants that involve more than two breakpoints. BCAs occur at a significant frequency in both healthy and diseased individuals, affecting about 1 in every 500 newborns (0.2%) (Ravel et al, 2006; Blake et al, 2014) These babies have an increased risk of multiple congenital anomalies, autism spectrum disorders (ASD), or intellectual disability (ID) (Marshall et al, 2008; Blake et al, 2014). A figure of 3.7–9.4% is generally quoted as the overall risk of developing a congenital anomaly when a de novo BCA is identified (Warburton, 1991)
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