P-736 Balanced cryptic chromosomal rearrangement carriers detection by optical genome mapping (OGM)
Authors: Yan J , Li Y , Chen K , Xu Y , Yang J , Xu Y , Wu Z 
Published: June 2023

Study question

To evaluate diagnosis value of optical genome mapping (OGM) for potential preimplantation genetic testing in chromosomal structural rearrangement (PGT-SR) patients with cryptic chromosomal rearrangement.

Summary answer

OGM is an efficient method for cryptic chromosomal rearrangement detection. However, SVs near telomere and centromere regions could hardly be reported with this method.

What is known already

About 5∼10% infertility or sterility people carry balanced chromosomal structural variations (SVs) with high risks of miscarriage and birth defects resulting from imbalanced gametes when producing fetus. However, some balanced cryptic SVs with specific location or small fragments cannot be detected by traditional cytogenetic techniques like G-banding testing or CNV-seq. Currently, several optimized techniques are able to detect typically cryptic structural abnormality. OGM, the molecular genetic detection technique relying on new principle in recent years, have overcome the shortcomings of former techniques and are potentially capable to detect both routine and cryptic SVs well.

Study design, size, duration

From 2019 to 2022, 12 couples in The First Affiliated Hospital of Sun Yat-sen University and The First People’s Hospital of Yunnan Province with history of offspring birth defect, recurrent unexplained recurrent miscarriage or unexpected copy number variation in embryos from previous PGT cycles were included for diagnosis or re-analysis.

Participants/materials, setting, methods

Peripheral blood lymphocytes from these patients were collected and detected by OGM or traditional karyotype analysis(G-400 banding), FISH, CNV-seq, third generation sequencing(Nanopore). The results of traditional genetic test and OGM were compared to evaluate the accuracy of OGM detection of chromosomal structure vatiation.

Main results and the role of chance

In the 11 couples bearing adverse pregnancy or childbirth defect with normal karyotype by G-banding, OGM discovered novel chromosome translocations or inversion in 9 couples (81.81%). In 1 couple with t(4:17)(q12;p13) diagnosed by G-banding, OGM detect an additional chromosomal translocation of t(17;19)(q12;p13), which produced the repeated CNVs in chromosome19 observed in embryos from two previous PGT cycles. For small fragment translocation, terminal translocation and inversion, OGM is able to detected balanced structure abnormal of 500kbs. The OGM diagnosis were confirmed by FISH or third generation sequencing (Nanopore) or embryo mutation. The breaking position reported by OGM and Nanopore were comparable. In sum, OGM reported further information of balanced SVs in 83.33% (10/12) potential patients with duplication and depletion in embryos or abortus.

Limitations, reasons for caution

Due to the limitation of principle, the structural abnormalities of some special locations (centromere, secondary constriction, etc.) cannot be detected. OGM has high sensitivity and many mutations, which requires examiners to have strong ability to analyze results and genetic counseling. The price of OGM also limits the promotion and application.

Wider implications of the findings

OGM can provide more precious result for SVs, and PGT-SR can definitely improve the outcome of certain population with cryptic chromosomal rearrangements. The shortcoming of OGM has not been overcame yet, so it is suggested as auxiliary method beside conventional G-binding in certain circumstances in ART population.

Trial registration number

Not applicable