Abstract
BACKGROUND: Chromosomal microarray analysis (CMA) is being increasingly used to reveal the genetic causes of miscarriage. Nevertheless, approximately half of the time it cannot produce a clear diagnosis. This study aims to investigate the genetic etiology of miscarriage by combining the use of CMA and whole-exome sequencing (WES). METHODS: A total of 172 pregnant Chinese women who had suffered miscarriages were enrolled in this study. However, those who had received assisted reproductive services were excluded. Among them, 32 cases without pathogenic copy number variants were further subject to WES analysis, then the relevant variants were confirmed by Sanger sequencing. RESULTS: Of the 172 enrolled subjects, CMA was successfully performed in 158 cases, with a detection rate of 91.86%. Among them, 82 cases had chromosomal numerical abnormalities. The most common abnormality was chromosome aneuploidy, followed by triploidy and mosaicism. In addition, nine cases carrying pathogenic copy number variants were also identified. Furthermore, WES detection revealed 11 candidate genes that may have caused miscarriage, including the F5, ANXA5, FGA, NSDHL, ATP8B1, JAK2, CC2D2A, FOXP1, CALCRL, TLE6, and CHRNA1 genes. CONCLUSIONS: Our findings strengthen that CMA is a rapid and effective genetic etiology diagnosis tool for miscarriages, producing the highest chromosomal abnormality detection rate at a gestational age of 10-11(+6) weeks. In addition, several gene variants were identified using WES, which may expand the mutation spectrum for miscarriage and provide more valuable information in understanding the phenotype and genotype correlations.