Clinical application of preimplantation genetic testing based on low-coverage next-generation sequencing with linkage...

In order to explore the clinical effect of preimplantation genetic testing (PGT) in hereditary hearing loss (HHL), we explore the related factors affecting the pregnancy outcome of PGT of hereditary hearing loss and provide more evidence for clinical work.

From January 2015 to April 2024, we select 288 couples of child-bearing age who are at risk of conceiving children with HHL from 1444 pedigrees in Chinese Deafness Genome Project (CDGP). After genetic counseling, 19 couples elected to undergo PGT. The embryo genotypes were diagnosed by low-coverage sequencing combined with SNP linkage analysis, and followed up during pregnancy and after delivery.

The 19 couples include variants of autosomal recessive hearing loss gene GJB2, SLC26A4, USH2A, CDH23, and autosomal dominant hearing loss gene MITF, WFS1, and GSDME. The 135 embryos from the 19 couples were cultured in vitro, 93.33% (126/135) embryos got reliable genetic diagnosis, and nine embryos (6.67%) had no diagnosis. The depth of embryonic 2-3 × WGS of 205 human hearing loss genes are sufficient. Eleven women got pregnancy, and eight newborns with normal hearing have been delivered through assisted reproduction; clinical pregnancy rate was 57.89% (11/19). Pregnancy outcome is associated with the female age (P = 0.037), male age (P = 0.015), and number of transferable blastocysts obtained (P = 0.000) in per ART cycle.

PGT based on low-coverage next-generation sequencing with linkage analyses can block the transmission of deafness-related mutations to offspring. 2-3 × depth of embryo sequencing data enabled a credible testing of 205 deafness-related mutations loci. Couple age and number of retrieved oocytes are related to pregnancy outcome and can be considered prognostic indicators of PGT of HHL.