Clinical application of SNP array analysis in first‐trimester pregnancy loss: a prospective study

Abstract

Chromosomal microarray analysis (CMA) has been used routinely in pediatric and prenatal genetic diagnosis in clinical practice, but it has rarely been applied to miscarriage analysis. In this study, we conducted a prospective study to evaluate the feasibility of CMA for genetic diagnosis of first-trimester miscarriage specimens. We successfully analyzed 551 fresh miscarriage specimens using single-nucleotide polymorphism (SNP) array. Among the specimens, 2.9% (16/551) had significant maternal cell contamination and were excluded from the study. Clinically significant chromosomal abnormalities were identified in 295 (55.1%) cases, including 214 (40%) with aneuploidy, 40 (7.5%) with polyploidy, 19 (3.6%) with partial aneuploidy, 12 (2.2%) with pathogenic microdeletion/microduplication, and 10 (1.9%) with uniparental isodisomy (isoUPD). Variants of uncertain significance were obtained in 15 cases (2.8%). Notably, isoUPD involving a single chromosome (chromosome 22) and two recurrent copy number variations, 22q11.2 microdeletion and 7q11.23 microdeletion, were identified as probably to be associated with miscarriage. The frequency and distribution of genetic aberrations in the spontaneous abortion group was not significantly different from those in the recurrent miscarriage group. Our study suggests SNP array is a reliable, robust, and high-resolution technology for genetic diagnosis of miscarriage in clinical practice.

Added value of chromosomal microarray analysis over karyotyping in early pregnancy loss: systematic review and meta‐analysis

“…The search identified 630 articles, 29 of which were full-text reviewed and 20 of those were finally included in the meta-analysis 9,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] . Nine studies were excluded either because reported data could not be extracted, or identification of the gestational age or indication for sampling for each case was not provided (if late pregnancy losses or other indications for CMA were included, respectively), or if only morphologically abnormal embryos were included or could not be identified (Table S2).…”

“…The main characteristics of the 23 studies included in the meta-analysis are outlined in Table 1. Ten studies included only first-trimester pregnancy losses 9,20,22,23,25,30,35,37,38,40 and 13 included losses under 20 weeks 19,21,24,[26][27][28][29][31][32][33][34]36,39 . In six studies, CMA was performed after a normal karyotype or QF-PCR result, in seven studies it was performed concurrently to karyotyping, and in the remaining 10 as a first-tier technique.…”

“…Only for cases with normal karyotype was the incremental yield over karyotyping assessed. Seven studies included samples of recurrent pregnancy losses 27,30,[35][36][37][38][39] . Quality assessment of the included studies using QUADAS-2 is shown in Figure 2.…”

“…After stratification of series according to inclusion of recurrent pregnancy loss, the mean incremental yield in the seven series with recurrent losses was 2% (66/3691) (95% CI, 1-2%) ( Figure S3), while in the 18 series with no recurrent loss, it was 1% (40/1816) (95% CI, 1-2%) ( Figure S4). Among 106 pathogenic CNVs overall, 48 were specified in 16 of the series (Table 3), their size ranged between 100 kb and 11 Mb, and the most frequently found were del22q11.21 (n = 4) 26,31,32,37 , and dup10q26 (n = 3) 19,28,37 . The following CNVs were found in two cases each: del1p36.33 28,35 , del7q11.23 26,37 , dup11p15.5 26 , del22p13 26 , and del3p26 20,37 .…”

Combination of QF‐PCR and aCGH is an efficient diagnostic strategy for the detection of chromosome aberrations in recurrent miscarriage

“…On the other hand, unbalanced structural rearrangements comprise less than 10% of all chromosome aberrations in POCs of couples with RM (Carp et al, ; Choi et al, ; Liu et al, ; Ozawa et al, ; Robberecht et al, ; Stephenson et al, ; Sugiura‐Ogasawara et al, ; Sullivan et al, ; Wang et al, ). We detected large rearrangements in three POCs resulting in partial trisomies of chromosomes 11q13, 7q32, and 2q22, as well as partial monosomies of chromosomes 17p13, 3p26, and 13q31, respectively.…”