Identification of a familial complex chromosomal rearrangement by optical genome mapping

Yang, Yang; Wang, Hao

doi:10.1186/s13039-022-00619-9

Cited by 6 publications

(4 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to these techniques, OGM has extremely high resolution and is capable of comprehensively detecting balanced and unbalanced SVs as small as 30 kb [ 17 ], which are unprecedented with karyotyping and CMA. For this reason, OGM has tremendous potential for the discovery of genetic causes of infertility, recurrent spontaneous abortion and histories of adverse pregnancy outcomes, as shown in this and other studies [ 7 , 8 , 16 ].…”

Section: Discussionmentioning

confidence: 79%

Identification of complex and cryptic chromosomal rearrangements by optical genome mapping

et al. 2023

View full text Add to dashboard Cite

Background Optical genome mapping (OGM) has developed into a highly promising method for detecting structural variants (SVs) in human genomes. Complex chromosomal rearrangements (CCRs) and cryptic translocations are rare events that are considered difficult to detect by routine cytogenetic methods. In this study, OGM was applied to delineate the precise chromosomal rearrangements in three cases with uncertain or unconfirmed CCRs detected by conventional karyotyping and one case with a cryptic translocation suggested by fetal chromosomal microarray analysis (CMA). Results In the three cases with CCRs, OGM not only confirmed or revised the original karyotyping results but also refined the precise chromosomal structures. In the case with a suspected translocation not detected by karyotyping, OGM efficiently identified the cryptic translocation and defined the genomic breakpoints with relatively high accuracy. Conclusions Our study confirmed OGM as a robust alternative approach to karyotyping for the detection of chromosomal structural rearrangements, including CCRs and cryptic translocations.

show abstract

Section: Discussionmentioning

confidence: 79%

Identification of complex and cryptic chromosomal rearrangements by optical genome mapping

et al. 2023

View full text Add to dashboard Cite

show abstract

“…A vast majority of studies have demonstrated the utility of OGM in detecting nearly all types of chromosomal aberrations and highlighted its clinical superiority to SOC assays in detecting complex cryptic SVs. In assisted reproduction, OGM has been used to clarify the etiology of infertility, recurrent spontaneous abortion, and abnormal pregnancy histories ( Wang et al, 2020 ; Yang and Hao, 2022 ; Zhang et al, 2022 ). This technology not only helps optimize reproductive decisions but also avoids the birth of children with severe genetic diseases.…”

Section: Discussionmentioning

confidence: 99%

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

Xie,

Xue,

Zhang

et al. 2023

Front. Genet.

View full text Add to dashboard Cite

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.

show abstract

“…This is the case for subchromosomal-size inversions for which OGM has been shown to be much more frequent than previously estimated ( Porubsky et al, 2022 ). OGM highlights that even copy-neutral insertions increase the burden of genetic disorders, demonstrating that some of them are found in regions refractory to sequencing ( Sabatella et al, 2021 ; Yang and Hao, 2022 ; Zhang et al, 2023 ). A separate condition concerns the so-called copy-neutral loss-of-heterozygosity (CN-LoH).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Decrypting an interchromosomal insertion associated with Marfan’s syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants

Bonaglia,

Salvo,

Sironi

et al. 2023

Front. Genet.

View full text Add to dashboard Cite

Optical genome mapping (OGM), which allows analysis of ultra-high molecular weight (UHMW) DNA molecules, represents a response to the restriction created by short-read next-generation-sequencing, even in cases where the causative variant is a neutral copy-number-variant insensitive to quantitative investigations. This study aimed to provide a molecular diagnosis to a boy with Marfan syndrome (MFS) and intellectual disability (ID) carrying a de novo translocation involving chromosomes 3, 4, and 13 and a 1.7 Mb deletion at the breakpoint of chromosome 3. No FBN1 alteration explaining his Marfan phenotype was highlighted. UHMW gDNA was isolated from both the patient and his parents and processed using OGM. Genome assembly was followed by variant calling and annotation. Multiple strategies confirmed the results. The 3p deletion, which disrupted ROBO2, (MIM*602431) included three copy-neutral insertions. Two came from chromosome 13; the third contained 15q21.1, including the FBN1 from intron-45 onwards, thus explaining the MFS phenotype. We could not attribute the ID to a specific gene variant nor to the reshuffling of topologically associating domains (TADs). Our patient did not have vesicular reflux-2, as reported by missense alterations of ROBO2 (VUR2, MIM#610878), implying that reduced expression of all or some isoforms has a different effect than some of the point mutations. Indeed, the ROBO2 expression pattern and its role as an axon-guide suggests that its partial deletion is responsible for the patient’s neurological phenotype. Conclusion: OGM testing 1) highlights copy-neutral variants that could remain invisible if no loss of heterozygosity is observed and 2) is mandatory before other molecular studies in the presence of any chromosomal rearrangement for an accurate genotype-phenotype relationship.

show abstract

Identification of a familial complex chromosomal rearrangement by optical genome mapping

Cited by 6 publications

References 23 publications

Identification of complex and cryptic chromosomal rearrangements by optical genome mapping

Identification of complex and cryptic chromosomal rearrangements by optical genome mapping

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

Case Report: Decrypting an interchromosomal insertion associated with Marfan’s syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants

Contact Info

Product

Resources

About