A comprehensive and universal approach for embryo testing in patients with different genetic disorders

Zhang, Shuo; Chen, Lei; Wu, Junping; Xiao, Min; Zhou, Jing; Zhu, Senlai; Fu, Jing; Lu, Daru; Sun, Xiaoxi; Xu, Congjian

doi:10.1002/ctm2.490

Cited by 25 publications

(16 citation statements)

References 48 publications

(137 reference statements)

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“…Balanced genomic aberrations, such as balanced translocations and inversions, can cause abnormal phenotypes when the expression or function of critical genes is affected 28. Although most balanced rearrangements carriers show no discernible clinical phenotype, the risk of miscarriage or delivering newborns with chromosomal imbalances is increased in this population because of the unbalanced gametes generated by recombinant chromosomes during meiosis 29 30. Moreover, X-autosome translocation is related to gonadal dysfunction and premature ovarian failure when breakpoints are localised in regions of the X chromosome that are critical for ovarian functions 31.…”

Section: Discussionmentioning

confidence: 99%

Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping

et al. 2022

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BackgroundChromosomal rearrangements have profound consequences in diverse human genetic diseases. Currently, the detection of balanced chromosomal rearrangements (BCRs) mainly relies on routine cytogenetic G-banded karyotyping. However, cryptic BCRs are hard to detect by karyotyping, and the risk of miscarriage or delivering abnormal offspring with congenital malformations in carrier couples is significantly increased. In the present study, we aimed to investigate the potential of single-molecule optical genome mapping (OGM) in unravelling cryptic chromosomal rearrangements.MethodsEleven couples with normal karyotypes that had abortions/affected offspring with unbalanced rearrangements were enrolled. Ultra-high-molecular-weight DNA was isolated from peripheral blood cells and processed via OGM. The genome assembly was performed followed by variant calling and annotation. Meanwhile, multiple detection strategies, including FISH, long-range-PCR amplicon-based next-generation sequencing and Sanger sequencing were implemented to confirm the results obtained from OGM.ResultsHigh-resolution OGM successfully detected cryptic reciprocal translocation in all recruited couples, which was consistent with the results of FISH and sequencing. All high-confidence cryptic chromosomal translocations detected by OGM were confirmed by sequencing analysis of rearrangement breakpoints. Moreover, OGM revealed additional complex rearrangement events such as inverted aberrations, further refining potential genetic interpretation.ConclusionTo the best of our knowledge, this is the first study wherein OGM facilitate the rapid and robust detection of cryptic chromosomal reciprocal translocations in clinical practice. With the excellent performance, our findings suggest that OGM is well qualified as an accurate, comprehensive and first-line method for detecting cryptic BCRs in routine clinical testing.

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Section: Discussionmentioning

confidence: 99%

Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping

et al. 2022

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“… 7 , 8 In recent years, our team has illustrated haplotype analysis can also accurately detect balanced and unbalanced chromosome structural rearrangements in human embryos through PGT. 9 The concept that foetal karyotypes can be predicted by inherited parental haplotypes was first introduced for NIPT in this study. The general workflow of our study was illustrated in Figure 1A .…”

Section: Figurementioning

confidence: 99%

A novel noninvasive prenatal testing method for chromosomal rearrangements using maternal circulating cell‐free foetal DNA

Zhang

Pei

Chen

et al. 2023

Clinical & Translational Med

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Dear Editor, At present, there is no noninvasive prenatal testing (NIPT) method available for pregnant women that one partner of couples carry balanced chromosomal rearrangements (BCRs). Here we present a novel NIPT method for detecting foetal chromosomal rearrangements based on haplotype analysis of maternal cell-free foetal DNA (cffDNA) and demonstrate its effectiveness and potential for clinical application in a cohort of 46 patients.BCRs are estimated to occur in approximately 0.5% of newborn infants 1 and the prevalence is even up to 4%-5% in individuals with fertility problems. 2 BCRs can result in infertility, recurrent miscarriages, or offspring with congenital malformations. 3,4 In general, invasive prenatal diagnosis (IPD) such as amniocentesis is recommended after pregnancy for couples in which one partner carries BCRs. However, IPD poses a 0.5% risk of miscarriage, infection and preterm labour. 5 Therefore, many couples decline IPD despite being BCR carriers. During pregnancy, maternal plasma contains a small percentage of cffDNA, which is an easily accessible source for the noninvasive determination of foetal chromosomal anomalies. The discovery has presented the possibility of noninvasive testing for genetic diseases; NIPT is now being increasingly used for detecting foetal chromosomal aneuploidies and monogenic disorders. 6,7 However, NIPT for structural chromosomal rearrangements (NIPT-SR) has not been available until now, despite its relatively high incidence.Core family-based haplotype linkage analysis has long been used to indirectly diagnose monogenic diseases, such as in preimplantation genetic testing (PGT) and NIPT. 7,8 In recent years, our team has illustrated haplotype analysis can also accurately detect balanced and unbalanced chromosome structural rearrangements in human embryos through PGT. 9 The concept that foetal karyotypes can be predicted by inherited parental haplotypes was first introduced for NIPT in this study. The general workflow of ourThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…However, 20 samples with inconclusive calls suggested the biological limitations of OnePGT, which requires additional family members for haplotyping. Zhang et al reported a method based on family haplotype linkage analysis (FHLA) and cnvPartition as the core algorithm to accurately detect a broad spectrum of monogenic diseases, aneuploidy, and chromosome abnormalities in embryos [78] . For 59 embryos, aneuploidies were analyzed using SNP allele frequency and the log R ratio, monogenic disorder and chromosomal rearrangements were detected by haplotypes located within the 2 Mb region covering the targeted genes or breakpoint regions.…”

Section: Pgt-plus As a Comprehensive Pgtmentioning

confidence: 99%

A review of pre-implantation genetic testing technologies and applications

Zhao

Kang

et al. 2022

Reproductive and Developmental Medicine

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The first practice of pre-implantation genetic testing (PGT) was reported more than 30 years ago. PGT, originally named pre-implantation genetic screening (PGS) and pre-implantation genetic diagnosis (PGD), is now categorized as PGT for aneuploidies (PGT-A), PGT for monogenic/single-gene defects (PGT-M), and PGT for chromosomal structural rearrangements (PGT-SR). Patients with fertility issues caused by advanced maternal age, carrier status of chromosomal abnormalities, or harboring pathogenic variant(s) are recommended to undergo PGT to increase the possibility of successful live birth and avoid potentially affected newborns. High-throughput techniques, such as DNA microarrays and next-generation sequencing (NGS), have enabled comprehensive screening of all 24 chromosomes, instead of few loci at a time. Furthermore, as a comprehensive PGT, PGT-Plus was enabled by the rapid development of a genome-wide single-cell haplotyping technique to detect embryo aneuploidy, single-gene disorders, and chromosomal aberrations simultaneously using a single universal protocol. In addition, non-invasive approaches enable a more intact embryo during the biopsy procedure, which may avoid potential mosaicism issues at a certain scale by testing spent culture media (SCM). As a novel PGT application, PGT-P detects genome-wide variations in polygenic diseases, which account for a large proportion of premature human deaths and affect a markedly larger population than monogenic diseases, using polygenic risk score calculation to decrease the potential of affecting complex conditions. Owing to the emergence of new technologies recruited to PGTs, more couples with infertility issues have a promising chance of conceiving a healthy baby, ultimately facilitating the human species to live more prosper.

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A comprehensive and universal approach for embryo testing in patients with different genetic disorders

Cited by 25 publications

References 48 publications

Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping

Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping

A novel noninvasive prenatal testing method for chromosomal rearrangements using maternal circulating cell‐free foetal DNA

A review of pre-implantation genetic testing technologies and applications

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