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Updated: Aug 6, 2026
Pre-Implantation Genetic Testing for Aneuploidy on a Semiconductor Based Next-Generation Sequencing Platform
Published on: August 17, 2022
Preimplantation Genetic Testing for Cornelia de Lange Syndrome with Low-Level Maternal Gonadal Mosaicism for a
Lulu Meng1, Yan Wang1, Junqiang Zhang2
1Department of Prenatal Diagnosis, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), Nanjing, Jiangsu, People's Republic of China.
Purpose:
To diagnose and perform preimplantation genetic testing for monogenic disorders (PGT-M) in a Chinese family affected by Cornelia de Lange syndrome type 5, resulting from a microdeletion in Xq13.1q13.2 truncating the HDAC8 gene characterized by low-level gonadal mosaicism.
Patients And Methods:
A de novo copy number variation (CNV) was identified through chromosomal microarray analysis and whole exome sequencing in a family with two unsuccessful pregnancies, indicating germline mosaicism. The CNV was validated via real-time quantitative PCR. Whole-genome low-coverage mate-pair sequencing was conducted on female peripheral blood to exclude chromosomal abnormalities. Long-PCR amplified the deleted fragment, utilizing primers designed nearby breakpoints identified through chromosomal microarray analysis. Oxford Nanopore Technology sequencing pinpointed specific breakpoint positions. Droplet-digital PCR (ddPCR) confirmed germline mosaicism in ovarian samples.
Results:
A female patient, suspected of harboring a de novo microdeletion at Xq13.1q13.2 exhibiting gonadal mosaicism, along with her husband, participated in this study. The diagnoses of the 172.3 kb microdeletion at Xq13.1q13.2 as low-level gonadal mosaicism was corroborated through nanopore sequencing and ddPCR. We constructed the high-risk haplotype using the affected products of conception as the phasing reference, and performed PGT-M based on SNP haplotype linkage analysis, finally achieving a healthy live birth in February 2023.
Conclusion:
Our findings underscore the efficacy of PGT-M employing haplotype linkage analysis for CNVs less than 1 Mb, even within cases involving gonadal mosaicism. We present methodologies to address microdeletions associated with gonadal mosaicism utilizing next-generation sequencing, microarray, nanopore sequencing and ddPCR techniques. Our results advocate for an expansion of PGT-M based on haplotype linkage analysis for families with minor pathogenic CNVs.
