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Case Reports
. 2023 Sep 7:14:1248544.
doi: 10.3389/fgene.2023.1248544. eCollection 2023.

Combination of trio-based whole exome sequencing and optical genome mapping reveals a cryptic balanced translocation that causes unbalanced chromosomal rearrangements in a family with multiple anomalies

Min Xie #  1 , Jiangyang Xue #  1 , Yuxin Zhang  1 , Ying Zhou  1 , Qi Yu  2 , Haibo Li  1 , Qiong Li  2
Affiliations
Case Reports

Combination of trio-based whole exome sequencing and optical genome mapping reveals a cryptic balanced translocation that causes unbalanced chromosomal rearrangements in a family with multiple anomalies

Min Xie et al. Front Genet. .

Abstract

Background: Balanced translocation (BT) carriers can produce imbalanced gametes and experience recurrent spontaneous abortions (RSAs) and even give birth to a child with complex chromosomal disorders. Here, we report a cryptic BT, t(5; 6) (p15.31; p25.1), in the proband's grandmother, which caused unbalanced chromosomal rearrangements and various anomalies in the two subsequent generations. We also provide a thorough overview of the application of optical genome mapping (OGM) to identify chromosomal structural variants (SVs). Methods: Trio-based whole exome sequencing (Trio-WES) was conducted to explore the genetic basis of the phenotype of the proband and her mother. High-resolution karyotype analysis and OGM detection were performed on the proband's grandparents to trace the origin of the unbalanced rearrangements between chromosomes 5 and 6. A PubMed search was conducted with the following keywords: "OGM" and "SVs." Then, relevant studies were collected and systematically reviewed. Results: The proband and her mother presented with various anomalies, whereas the grandmother was healthy but had a history of four abnormal pregnancies. Trio-WES revealed a heterozygous duplication on the terminal region of chromosome 5p and a heterozygous deletion on the proximal end of chromosome 6p in the proband and her mother. High-resolution karyotype analysis revealed no aberrant karyotypes in either grandparent, whereas OGM detection revealed a cryptic BT, t(5; 6)(p15.31; p25.1), in the proband's grandmother. An overwhelming majority of research publications have verified the clinical utility of OGM in detecting SVs. Conclusion: The results of this study revealed that the unbalanced chromosomal rearrangements and many anomalies observed in multiple members of the family were attributable to the cryptic BT carried by the proband's grandmother. This study supports that OGM has a unique advantage for detecting cryptic BTs, and can be used as a first-tier genetic test for the etiological diagnosis of infertility, RSAs, and other complex genetic disorders.

Keywords: case report; cryptic balanced translocation; multiple anomalies; optical genome mapping; unbalanced chromosomal rearrangements.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The pedigree chart and results of trio-WES. (A) The pedigree chart of this family: black represents the patients, arrow represents the proband, half-blackened circle represents the carrier of BT, oblique line represents the died; (B) The quantified CNVs of trio-WES for the proband and her mother; (C) The copy number of WES_5p15.33-5p15.32 and WES_6p25.3-6p25.1 in this family: III-1 represents the proband, II-1 represents the proband’s father, II-2 represents the proband’s mother.
FIGURE 2
FIGURE 2
The results of high-resolution karyotype analysis and OGM analysis for the proband’s grandparents. (A) The description of grandmother’s karyotype was shown as 46,XX; (B) The description of grandfather’s karyotype was shown as 46,XY; (C) A cryptic BT between chromosomes 5 and 6 was uncovered in the grandmother by OGM: red arrow represents OGM analysis result; (D) No abnormity was found in the grandfather by OGM.
FIGURE 3
FIGURE 3
The visual BT results of OGM in the grandmother. (A) According to the breakpoint, the whole chromosome 5 was separated into Chr5-A and Chr5-B, and the whole chromosome 6 was separated into Chr6-A and Chr6-B; (B) The derived chromosome 5 comprises Chr6-A (6pter-6p25.1, 5.025 M) and Chr5-B (5p15.31-5qter, 174.599 M), and the derived chromosome 6 comprises Chr5-A (5pter-5p15.31, 6.301 M) and Chr6-B (6p25.1-6qter, 166.075 M).
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Grants and funding

This study was funded by the Zhejiang Provincial Medical and Healthcare Program (Grant No. 2022KY1157), Ningbo public welfare project (Grant Nos 2022S035 and 202002N3150), Innovation Project of Distinguished Medical Team in Ningbo (Grant No. 2022020405).

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