Association of prenatal renal ultrasound abnormalities with pathogenic copy number variants in a large Chinese cohort

Abstract

Objectives To assess the clinical utility of prenatal chromosomal microarray analysis (CMA) in fetuses with abnormal renal sonographic findings, and to evaluate the association of pathogenic or likely pathogenic copy number variants (P/LP CNVs) with different types of renal abnormality. Methods This was a retrospective study of fetuses at 14–36 weeks screened routinely for renal and other structural abnormalities at the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region. We retrieved and analyzed data from fetuses with abnormal renal sonographic findings, examined between January 2013 and November 2019, which underwent CMA analysis using tissue obtained from chorionic villus sampling (CVS), amniocentesis or cordocentesis. We evaluated the CMA findings according to type of renal ultrasound anomaly and according to whether renal anomalies were isolated or non‐isolated. Results Ten types of renal anomaly were reported on prenatal ultrasound screening, at a mean ± SD gestational age of 24.9 ± 4.8 weeks. The anomalies were diagnosed relatively late in this series, as 64% of cases with an isolated renal anomaly underwent cordocentesis rather than CVS. Fetal pyelectasis was the most common renal ultrasound finding, affecting around one‐third (34.32%, 301/877) of fetuses with a renal anomaly, but only 3.65% (n = 11) of these harbored a P/LP CNV (comprising: isolated cases, 2.37% (4/169); non‐isolated cases, 5.30% (7/132)). Hyperechogenic kidney was found in 5.47% (n = 48) of fetuses with a renal anomaly, of which 39.58% (n = 19) had a P/LP CNV finding (comprising: isolated cases, 44.44% (16/36); non‐isolated cases, 25.00% (3/12)), the highest diagnostic yield among the different types of renal anomaly. Renal agenesis, which accounted for 9.92% (n = 87) of all abnormal renal cases, had a CMA diagnostic yield of 12.64% (n = 11) (comprising: isolated cases, 11.54% (9/78); non‐isolated cases, 22.22% (2/9); unilateral cases, 11.39% (9/79); bilateral cases, 25.00% (2/8)), while multicystic dysplastic kidney (n = 110), renal cyst (n = 34), renal dysplasia (n = 27), crossed fused renal ectopia (n = 31), hydronephrosis (n = 98), renal duplication (n = 42) and ectopic kidney (n = 99) had overall diagnostic rates of 11.82%, 11.76%, 7.41%, 6.45%, 6.12%, 4.76% and 3.03%, respectively. Compared with the combined group of CMA‐negative fetuses with any other type of renal anomaly, the rate of infant being alive and well at birth was significantly higher in CMA‐negative fetuses with isolated fetal pyelectasis or ectopic kidney, whereas the rate was significantly lower in fetuses with isolated renal agenesis, multicystic dysplastic kidney or severe hydronephrosis. The most common pathogenic CNV was 17q12 deletion, which accounted for 30.14% (22/73) of all positive CMA findings, with a rate of 2.51% (22/877) among fetuses with an abnormal renal finding. Fetuses with 17q12 deletion exhibited a wide range of renal phenotypes. Other P/LP CNVs in the recurrent region that were associated with prenatal renal ultraso...

The genetic landscape of copy number variation in a Vietnamese cohort of 5008 fetuses with clinical anomalies during pregnancy

“…Among autosomal aneuploidies, we observed the highest rate in chromosomes 21, 18, and 13 (Table 1). These ndings are consistent with those reported in Asian 23 and English 33 populations. [Please insert Fig.…”

“…Recently, to maximize diagnostic accuracy, CNV analysis has been applied to identify and con rm chromosomal abnormalities among fetuses with sonography-detected soft markers and fetal structural anomalies 15,16 . Many ultrasound soft markers such as echogenic intracardiac focus, echogenic bowel, fetal ventriculomegaly, hypoplastic/aplastic nasal bone, and nuchal translucency have been investigated for their relationships with abnormal CNVs [17][18][19][20][21][22][23][24][25] . Multiple congenital structural anomalies have been studied for their correlations with CNVs in early prenatal diagnosis [26][27][28][29][30][31][32][33][34][35][36][37] .…”

Low-pass genome sequencing reveals associations between copy number variations and fetal ultrasonographic anomalies and soft markers in a cohort of 43,721 fetuses

“…Our results support that CNV analysis should be performed in fetuses with structural anomalies, 19 especially for fetuses with cystic hygroma, fetal hydrops, and abdominal wall defect, as the yield of aneuploidy/pCNV in these three anomalies was 21.14%-38.64%. Among 12 isolated ultrasonographic anomalies, this study discovered several well-known pCNV-associated organ systems (cardiovascular, genitourinary, skeletal and central nervous systems), 15,25 and provided sufficient evidence for rarely reported associations between abdominal wall defect, facial and respiratory systems, and fetal growth restriction and pCNV (Table S4). Notably, we firstly revealed that isolated abdominal wall defect was strongly associated with pCNV, in addition to its known association with aneuploidy.…”

“…[9][10][11] Cardiovascular, genitourinary, skeletal, and central nervous system defects were reported to be most commonly associated with chromosomal aberrations. [12][13][14][15][16][17][18] Therefore, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recommend CMA as a first-tier test in the diagnostic evaluation of fetal structural abnormalities for fetuses undergoing prenatal diagnosis. 19 Additionally, previous studies have demonstrated that aneuploidy and pCNV were frequently presented in specific soft markers, such as increased nuchal translucency, ventriculomegaly, and thickened nuchal fold.…”

Association of prenatal thoracic ultrasound abnormalities with copy number variants at a single Chinese tertiary center

“…CMA is especially recommended when genetic analysis is performed in cases with fetal structural anomalies 7 . It has been reported that CMA discovered clinically significant genomic alterations in 6.5% of fetuses with single or multiple ultrasound abnormalities, 8 8.32% with renal abnormalities, 9 and 20.8% with cardiac abnormalities 10 . The diagnostic yield and clinical utility of CMA in cases of fetal thoracic abnormalities remain to be elucidated.…”