Detection of chromosomal abnormalities in spontaneous miscarriage by low‑coverage next‑generation sequencing

Abstract

chromosomal abnormalities (cas) can cause spontaneous miscarriage and increase the incidence of subsequent pregnancy loss and other complications. Presently, cas are detected mainly by array comparative genomic hybridization (cGH) and single nucleotide polymorphism microarrays. The present study developed a low-coverage next-generation sequencing method to detect cas in spontaneous miscarriage and assess its clinical performance. in total, 1,401 patients who had experienced an abortion were enrolled in the present study and divided into two groups. in group i, 437 samples that had been previously validated by array cGH were used to establish a method to detect cas using a semiconductor sequencing platform. in group ii, 964 samples, which were not verified, were assessed using established methods with respect to clinical significance. Copy number variant (CNV)-positive and euploidy samples were verified by array CGH and short tandem repeat profiling, respectively, based on quantitative fluorescent PCR. The low-coverage sequencing method detected CNVs >1 Mb in length and a total of 3.5 million unique reads. Similar results to array cGH were obtained in group I, except for six CNVs <1 Mb long. In group II, there were 341 aneuploidies, 195 CNVs, 25 mosaicisms and 403 euploi-dies. overall, among the 1,401 abortion samples, there were 536 aneuploidies, 263 CNVs, 34 mosaicisms, and 568 euploidies. Trisomies were present in all autosomal chromosomes. The most common aneuploidies were T16, monosomy X, T22, T15, T21 and T13. Furthermore, one tetrasomy 21, one CNV associated with Wolf-Hirschhorn syndrome, one associated with diGeorge syndrome and one associated with both Prader-Willi and Angelman syndromes were identified. These four cases were confirmed by short tandem repeat profiling and array CGH. Quantitative fluorescent PCR revealed nine polyploidy samples. The present method demonstrated equivalent efficacy to that of array CGH in detecting CNVs >1 Mb, with advantages of requiring less input dna and lower cost.

Chromosomal copy-number variation analysis of villous tissues using molecular karyotyping in early missed abortions

“…Chromosomal numerical anomaly is the most common genetic cause of spontaneous miscarriages [33]. Here, 615 cases (81.6%, 615/754) had numerical abnormalities, which is consistent with results from a recent report [34], including 531 cases (45.8%) of single chromosome aneuploidy and 31 (2.7%) cases of multiple aneuploidies (Table 2). The occurrence frequency of each chromosome aneuploidy was analyzed in all 531 cases in this study (Fig.…”

Genetic Diagnostic Yield and Novel Causal Genes of Congenital Heart Disease

“…The recurrence of monosomy X (in 3 cases) in our cohort might be one of the factors in high OR in female CHD cases. Fetuses diagnosed with CHD included cases not surviving to term in which chromosomal abnormalities were considered major causes (∼60% of spontaneous miscarriage) ( Daniely et al, 1998 ; Li et al, 2020 ), and the latest follow-up time of isolated CHD cases were focused on the fetal period (78.43%, 40/51). The aforementioned factors and the characteristics of our cohort led to the OR assessment results which reflect the genetic profile of an unselected sporadic CHD cohort.…”

Copy number variation characterization and possible candidate genes in miscarriage and stillbirth by next‐generation sequencing analysis

“…The results in the present study are similar to those of other studies. 37 , 38 , 39 Some genes in chromosome 16 have been associated with diseases such as thalassemia, 40 prenatal growth retardation, 41 abnormal fetal head circumference 42 and autism. 43 One study found that CNVs on chromosome 16 play an important role in the determination of developmental delay.…”