Genetic analysis of fetuses with DMD gene variations by low-depth whole-genome copy number variation sequencing
10.3760/cma.j.cn113903-20240122-00040
- VernacularTitle:低深度全基因组拷贝数变异测序产前诊断发现 DMD基因变异胎儿的遗传学分析
- Author:
Lina LIU
1
;
Zhihui JIAO
;
Huanan REN
;
Xiangdong KONG
Author Information
1. 郑州大学第一附属医院遗传与产前诊断中心，郑州 450052
- Keywords:
Duchenne muscular dystrophy;
Prenatal diagnosis;
Low-depth whole-genome sequencing;
DMD gene
- From:
Chinese Journal of Perinatal Medicine
2024;27(10):836-841
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the significance and interpretation of low-depth whole-genome copy number variation sequencing (CNV-seq) in prenatal diagnosis in detecting DMD gene variations in fetuses without a family history of genetic diseases, and to investigate the results of family testing. Methods:Retrospectively collected case data of 16 fetuses with DMD gene deletions or duplications detected by low-depth whole-genome CNV-seq from December 2019 to August 2023 at the First Affiliated Hospital of Zhengzhou University. Amniotic fluid or chorionic villus samples and peripheral blood from family members were collected for all 16 cases, and genomic DNA was extracted. The fetal chromosomal copy number variations were detected using CNV-seq technology and the DMD gene deletions or duplications were verified by multiplex ligation-dependent probe amplification (MLPA), followed by family validation to trace the source of variation. The pathogenicity of the DMD gene deletion or duplication fragments was analyzed based on online Mendelian genetics databases and family validation results. Results:All 16 cases denied a family history of monogenic diseases. The indications for CNV-seq prenatal diagnosis were high-risk Down syndrome screening in nine cases, advanced maternal age in two cases, abnormal fetal ultrasound in three cases, and non-invasive prenatal DNA testing suggesting X chromosome abnormalities in two cases. CNV-seq results indicated nine cases of DMD gene duplication variations and seven cases of DMD gene deletion variations. MLPA validation confirmed results consistent with CNV-seq detection. Family analysis showed that three cases were de novo variations, 12 cases were inherited from the mother, one case had a mother with normal peripheral blood testing but a sister carrying the same variation, suggesting a high possibility of the mother being a carrier of gonadal mosaic. The likelihood of pathogenic variation was high in seven cases of deletion; nine cases were duplication variations, four of which were located within the DMD gene and could potentially disrupt the gene, leading to disease, while the other five variations were located in the 5' untranslated region or 3' untranslated region, considered benign variations. Conclusions:Low-depth whole-genome CNV-seq can effectively detect large deletion and duplication variations of the DMD gene in fetuses without a family history, preventing the birth of children with de novo variations. However, the pathogenicity of fetuses with large DMD gene duplications should be assessed based on family validation. When the duplication region includes the 5' untranslated region or 3' untranslated region of the DMD gene, it is more likely to be a polymorphic variation.
