P-547 Confined placental mosaicism for inherited segmental aneuploidies in miscarriages traces early karyotype self-correction events
Authors: Lebedev I , Drozdov G , Nikitina T , Sazhenova E , Tolmacheva E , Fonova E , Kashevarova A 
Published: June 2022

Study question

Does tissue-specific compartmentalization of segmental aneuploidies in first-trimester miscarriages reflect their postzygotic de novo origin or correction of inherited copy number variants (CNV)?

Summary answer

Most of mosaic CNVs (84%) in spontaneous abortions with normal karyotype arose de novo, but 16% resulted from postzygotic tissue-specific correction of maternally inherited variants.

What is known already

Chromosomal mosaicism is a hallmark of early human embryogenesis affecting significantly developmental potential of blastocysts, it’s implantation and delivery rates. Most of the currently available data are related to mosaic aneuploidies for a whole chromosome in IVF cycles, whereas little is known about origin and fate of mosaic segmental CNVs due to inherent limitations of NGS and aCGH for detection of copy number changes less for 5-10 Mb in size after single-cell whole genome amplification.

Study design, size, duration

Chorionic villi (CV) and extraembryonic mesoderm (EM) of miscarriages as well as maternal and paternal peripheral blood DNA samples were evaluated by aCGH+SNP arrays to detect the prevalence and tissue-specific distribution of segmental aneuploidies. As far as CV and EM are derivatives of trophectoderm and inner cell mass lineages, comparative analysis of both tissues allows to investigate the origin of mosaic CNVs by postzygotic de novo appearance or correction of the inherited variants.

Participants/materials, setting, methods

Eleven trios (mother, father, CV and EM samples from spontaneous abortion with normal karyotype by G-banding) were included in the study. Mean gestational age was 7.9 weeks. Mean maternal and paternal ages were 30.8 and 30.5 years, respectively. aCGH+SNP analysis was performed by SurePrint G3 Human CGH + SNP 4 × 180K microarrays (Agilent Technologies) with 13 kb median aCGH probes spacing.

Main results and the role of chance

Altogether 116 CNVs were detected in CV and EM samples from 11 abortions. Fifty four (46.6%) variants were present in both tissues, while 29 (25%) were confined by CV and 33 (28.4%) by EM. Most of tissue-specific segmental aneuploidies in CV (90%) and EM (79%) arose de novo, whereas others were inherited from parents. It is important that 5 maternally inherited microduplications in some clinically significant regions like 1p21.1 (103 kb in size), 2p21 (3.56 kb), 3p22.3 (128 kb), 7q36.3 (42.7 kb), and Xq28 (182 kb) were confined by EM, whereas two at 4p16.3 (22.3 kb) and 19q13.43 (2.2 kb) by CV. No cases of tissue-specific maternally inherited microdeletions or paternal CNVs were observed in our study. One can suggest that confined placental mosaicism for inherited maternal microduplications arisen by trisomy rescue mechanism with loss of additional maternal chromosome copy in CV or EM after its divergence around the time of blastocyst implantation. This hypothesis is confirmed by comparative SNP-haplotype analysis of DNA samples from both CV and EM tissues as well as parental samples in the subchromosomal regions of microduplications and adjusted loci.

Limitations, reasons for caution

Control group of induced (social) abortions of the same developmental terms are required to estimate the prevalence and distribution of mosaic segmental aneuploidies in embryonic and extraembrionic tissues during normal human embryo development.

Wider implications of the findings

Tracing of tissue-specific mosaic segmental aneuploidies in first-trimester miscarriages allows to estimate the level of karyotype instability and self-correction during human embryo development. This study was supported by the Russian Science Foundation, № 21-65-00017, https://rscf.ru/project/21-65-00017/

Trial registration number

not applicable