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Subchromosomal Anomalies in Small for Gestational-Age Fetuses And

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Archives of Gynecology and Obstetrics (2019) 300:633–639 https://doi.org/10.1007/s00404-019-05235-4 MATERNAL-FETAL MEDICINE Subchromosomal anomalies in small for gestational‑age fetuses and newborns Ying Ma1 · Yan Pei1 · Chenghong Yin2 · Yuxin Jiang3 · Jingjing Wang4 · Xiaofei Li4 · Lin Li5 · Karl Oliver Kagan6 · Qingqing Wu4 Received: 9 January 2019 / Accepted: 27 June 2019 / Published online: 4 July 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Purpose To analyze copy number variants (CNVs) in subjects with small for gestational age (SGA) in China. Methods A total of 85 cases with estimated fetal weight (EFW) or birth weight below the 10th percentile for gestational age were recruited, including SGA associated with structural anomalies (Group A, n = 20) and isolated SGA (Group B, n = 65). In all cases, cytogenetic karyotyping and infection screening were normal. We examined DNA from fetuses (amniocentesis or cordocentesis) and newborns (cord blood) to detect CNVs using a single nucleotide polymorphism (SNP, n = 75) array or low-pass whole-genome sequencing (WGS, n = 10). Results Of 85 total cases, 3 (4%) carried pathogenic chromosomal abnormalities, including 2 cases with pathological CNVs and 1 case with upd(22)pat. In Group A, the mean gestational age at the time of diagnosis was 26.8 (SD 4.1) weeks and mean EFW/birth weight was 907.2 (SD 567.8) g. In Group B, the mean gestational age at the time of diagnosis was 34.1 (SD 5.8) weeks. Mean EFW/birth weight was 1879.2 (SD 714.5) g. The pathologic detection rate was 10% (2/20) in Group A and 2% (1/65) in Group B. It was inclined that the lower the EFW percentile, the more frequent the occurrence of CNVs. Conclusions Pathological subchromosomal anomalies were detected by CMA or low-pass WGS in 10% and 2% of SGA subjects with and without malformation, respectively. SGA fetuses with structural anomalies presented with higher pathologi- cal subchromosomal anomalies. The molecular genetic analysis is not recommended for isolated SGA pregnancies without other abnormal fndings. Keywords Copy number variations · Small for gestational age · Single-nucleotide polymorphism array · Whole-genome sequencing Introduction * Qingqing Wu [email protected] The association of small-for-gestational-age (SGA) fetuses 1 Department of Obstetrics, Beijing Obstetrics with chromosomal abnormalities, especially trisomy 18 is and Gynecology Hospital, Capital Medical University, well established [1, 2]. However, there is still an ongoing Beijing 100026, China debate regarding whether copy number variants (CNVs) 2 Beijing Obstetrics and Gynecology Hospital, Capital Medical detected by molecular genetic tests such as chromosomal University, Beijing 100026, China microarray analysis (CMA) are more common in fetuses 3 Department of Ultrasound, Peking Union Medical College with SGA. Biron-Shental et al. [3] used single-nucleotide Hospital, Chinese Academy of Medical Sciences and Peking polymorphism (SNP) arrays to detect CNVs in placentas Union Medical College, Beijing 100730, China from small fetuses with normal anomaly scans and karyo- 4 Department of Ultrasound, Beijing Obstetrics types and healthy neonates. The authors identifed signif- and Gynecology Hospital, Capital Medical University, 251 cantly more genomic alterations in small fetal group and a Yaojia Yuan Road, Chaoyang District, Beijing 100026, China signifcant correlation between the size of the CNVs and the 5 Central Laboratory, Beijing Obstetrics and Gynecology severity of growth restriction [3]. Borrell et al. [4] exam- Hospital, Capital Medical University, Beijing 100026, China ined fetuses with isolated fetal growth below the 3rd cen- 6 Department of Women’S Health, University of Tuebingen, tile and with a normal cytogenetic karyotype, pathological Tübingen, Germany Vol.:(0123456789)1 3 634 Archives of Gynecology and Obstetrics (2019) 300:633–639 genomic imbalances were found in 4% of the cases. This Maternal and pregnancy characteristics and the results of rate was increased to 10% in those small fetuses’ cases with the antenatal examinations are entered into a digital data- additional defects [4]. A multicenter study revealed that base (Excel 2007, Microsoft, Richmond, USA). Data of after exclusion of aneuploides, in fetuses with early growth pregnancy outcome were followed up and were added after retardation (estimated fetal weight below the 3rd percen- delivery. tile before 32 weeks of pregnancy), pathogenic CNVs were The study cohort includes women with SGA pregnancies detected in 4.8%, 10%, and 10.5% of subjects having isolated between 2014 and 2016 where frst, cytogenetic karyotyping SGA, SGA with minor congenital anomalies and SGA with and infection screening were uneventful, second, where a major congenital anomalies, respectively [5]. CMA or a low-pass WGS was done and third, who agreed Ongoing research is focused on the extension of molecu- to participate in the study. lar genetic testing to whole-exome and -genome sequenc- ing. To date, experience with these methods is still limited, Molecular genetic follow-up examinations but in approximately 23–50% of cases with normal cytoge- netic and CMA results, whole-exome sequencing revealed From 2014 to 2015, CMA technology was used. To detect a chromosomal abnormality [6, 7]. Others have reported a CNVs the CytoScan™ 750D array (Afymetrix Inc., Santa 16% incremental CNVs yield by genome-wide screening in Clara, CA, USA) was used in combination with the CytoS- infants with prenatal and postnatal growth retardation asso- can™ 750D Reagent Kit. One array was used for each sam- ciated with dysmorphic features and/or developmental delay ple. The results were analyzed with Chromosome Analysis [8]. However, the high cost of WES and WGS limits their Suite (ChAS) software (Afymetrix, USA) using annotations wide use in clinical practice. CNVs is still one of screening of the genome version GRCH37 (hg19). The array detects methods with reasonable cost-efect. the sample at the resolution level of 50 kb/50 marker dele- In this study, we examined the proportion of pathogenic tion and 100 kb/50 marker repeat. subchromosomal anomalies in pregnancies with SGA fetuses In cases in which CNVs were detected in fetal or neonatal with and without structural defects, to investigate clinical DNA, DNA from the parents (peripheral blood) was exam- value of CNVs screening in both groups of SGA fetuses. ined using the same CytoScan™ 750D array to detect CNVs and establish whether the CNVs were de novo or inherited. In 2016, CNVs were detected by NGS technique, named low-pass whole genome sequencing (WGS). The DNA Methods library was prepared and subjected to deep sequencing using a NextSeq CN500 high-throughput sequencer. The detection Patients sensitivity of low-pass WGS is 100 kb. If Uniparental disomy (UPD) was detected, then link- Outpatient and inpatient singleton pregnant women treated age analysis by polymerase chain reaction (PCR)-based at Beijing Obstetrics and Gynecology Hospital of Capital Sequence-Tagged Site (STS) marker showed which one the Medical University between 2014 and 2016 were selected segmental isodisomy was of parental origin. for this study. Gestational age (GA) was assessed accord- The URLs for data presented herein are as follows: ing to the last menstrual period and the crown-rump length at 11–13 + 6 weeks. All these cases underwent a detailed • Database of Chromosomal Imbalance and Phenotype in ultrasound examination according to the practice guidelines Humans using Ensembl Resources (DECIPHER), https of the International Society of Ultrasound in Obstetrics and ://decip her.sange r.ac.uk/appli catio n/. Gynecology to detect structural anomalies. Fetal weight was • Database of Genomic Variants (DGV), https ://proje cts. estimated (EFW) according to the Hadlock II formula [9]. tcag.ca/varia tion/. An EFW or birth weight below the 10th percentile for GA • Database of Genotype and Phenotype, dbGaP, https :// was defned as SGA [10, 11]. An assessment of the maternal www.ncbi.nlm.nih.gov/gap. infection status (standard TORCH serology including Parvo • Database of Structural Variation, dbVAR, https ://www. virus B19) was performed in all cases. Furthermore, inva- ncbi.nlm.nih.gov/dbvar /. sive testing including cytogenetic karyotyping and CNVs • International Standard Cytogenomic Array Consortium, detection was recommended prenatally. In cases the parents https ://isca.genet ics.emory .edu. opted against invasive testing, above genetic examinations • Online Mendelian Inheritance in Man (OMIM), https :// were carried out after birth if requested. CNVs was detected www.ncbi.nlm.nih.gov/Omim. using CMA from 2014 to 2015, whereas in 2016 they were identifed by new generation sequencing (NGS), named low- All analysis results of CNVs and genes in this study pass whole genome sequencing(WGS). were interpreted by professionally certified clinical 1 3 Archives of Gynecology and Obstetrics (2019) 300:633–639 635 molecular geneticists or genetic experts. Pathological Results CNVs were assessed if they met the following criteria: gene content, overlap with genomic coordinates for a Clinical features known genomic imbalance syndrome, and overlap with a CNVs previously identified in FGR or short stature The study enrolled 85 pregnancies. There were 20 cases subjects. with a fetal defect (Group A) whereas in 65 cases, there was CNVs were classified according to the recommenda- isolated SGA (Group B). All families were of nonconsan- tion of the American College of Medical
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