Strategic study of preimplantation genetic testing for monogenic disorders with variants of uncertain significance
10.3760/cma.j.cn101441-20221012-00450
- VernacularTitle:单基因病临床意义不明变异实施植入前遗传学检测的策略研究
- Author:
Xiao HU
1
;
Juan DU
;
Zhenhua TAN
;
Weili WANG
;
Wenbin HE
;
Yueqiu TAN
;
Shuoping ZHANG
;
Jing DAI
;
Yi ZHANG
;
Zhenxing WAN
;
Wen LI
;
Keli LUO
;
Fei GONG
;
Guangxiu LU
;
Ge LIN
Author Information
1. 中信湘雅生殖与遗传专科医院，长沙 410000
- Publication Type:Journal Article
- Keywords:
Preimplantation genetic testing;
Monogenic disorders;
Variants of uncertain significance;
Reclassification
- From:
Chinese Journal of Reproduction and Contraception
2022;42(11):1121-1126
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the strategy of preimplantation genetic testing for monogenic disorders (PGT-M) with variants of uncertain significance (VUS).Methods:Monogenic disorder couples who carried VUS and sought fertility counseling between 2018 and 2020 in Reproductive and Genetic Hospital of CITIC-Xiangya were recruited in this study. The pathogenicity of VUS was reanalyzed according to the Standards and Guidelines for the Interpretation of Sequence Variants released by the American College of Medical Genetics and Genomics (ACMG) and the Bayesian Classification. Those VUSs were reclassified as "pathogenic/likely pathogenic variants (P/LP)", "likely pathogenic VUS", "variants of uncertain significance", or "likely benign VUS". PGT-M was applied to families with VUS upgraded as "P/LP" or "likely pathogenic VUS" under the principle of couples fully voluntary and understanding the risks. We also followed up the developmental status of fetuses and the health condition of the born children.Results:1) A total of 25 variants were detected in 16 families with monogenic disorders, including 1 P, 3 LP, and 21 VUS. After reanalysis, 11 VUS and 7 VUS were upgraded as LP (52.4%) and "likely pathogenic VUS" (33.3%), respectively. Two VUS were still reclassified as "variants of uncertain significance"(9.5%), and 1 VUS was reclassified as "likely benign VUS" (4.8%). 2) PGT-M was implemented for 14 families with monogenic disorders, including 9 families with VUS upgraded as LP, 2 families with one LP/P and one "likely pathogenic VUS", and 3 families with only "likely pathogenic VUS". 3) Twelve healthy babies were born after PGT-M. Following up was done according to the onset age of diseases: 8 offsprings did not show the symptoms as probands, and 4 offsprings had not yet reached the age of onset and need continuous follow-up.Conclusion:It is necessary to actively search for new evidence and reanalyze the pathogenicity of VUS according to ACMG guidelines before PGT-M. Under fully informed consent of the patients, PGT-M can be carried out for VUS reclassified as "P/LP" and "likely pathogenic VUS", to reduce the risk of recurrence.
