Background: Application of chromosomal microarray analysis (CMA) to investigate the genetic characteristics of fetal growth restriction (FGR) without ultrasonic structural anomalies at 18–32 weeks. Methods: This study includes singleton fetuses with the estimated fetal weight (EFW) using the formula of Hadlock C below the 10th percentile for gestational age. FGRs without structural anomalies were selected, and the ones at high risk of noninvasive prenatal testing for trisomy 13, 18 and 21 would be excluded. The cases were divided into two groups: early-onset group (< 24 weeks) and late-onset group (24–33 weeks). All patients were offered invasive prenatal testing with CMA and karyotype analysis. Results: CMA detected 10 pathogenic copy number variants and 2 variant of uncertain significance case. CMA has a 5.5% (7/127) incremental yield of pathogenic chromosomal abnormalities over karyotyping. The positive detected rate was 9.6% (5/52) in early-onset group and 9.3% (7/75) in late-onset group respectively. Conclusions: When FGR without structural anomaly is diagnosed before 33 weeks, an invasive prenatal procedure is strongly recommended. CMA can identify a 5.5% (7/127) incremental detection rate of pathogenic chromosomal abnormalities, which would impact clinical management for FGR. Keywords: Fetal growth restriction, Prenatal diagnosis, Chromosomal microarray, Karyotype analysis, Uniparental disomy Background been introduced into clinical practice, due to its high- Fetal growth restriction (FGR) is a common complica- resolution and whole-genome screening feature. Single- tion of pregnancy that has been associated with a variety nucleotide polymorphism (SNP) array, a CMA platform of adverse perinatal outcomes . Although many fac- used in prenatal diagnosis, can detect almost all genomic tors have been implicated in the process of fetal growth, imbalances recognized by karyotyping, as well as smaller the precise molecular and cellular mechanisms by which deletions and duplications in the kilobase (Kb) range, normal fetal growth occurs are still not well understood termed copy-number variants (CNV) . It has further .There is a strong association between FGR and facilitated the detection of uniparental disomy (UPD) chromosome aberrations. Fetuses with chromosome dis- , which could also be a potential cause of FGR . orders, including aneuploidy, duplication and deletion, CMA can detect a potentially pathogenic CNV in an are frequently growth restricted . additional 6–7% of cases with fetal structural abnormal- Although conventional karyotyping is the current gold ities detected by ultrasound .The American Congress standard for prenatal cytogenetic analysis for several de- of Obstetricians and Gynecologists (ACOG) and the So- cades, chromosomal microarray analysis (CMA) has ciety for Maternal-fetal Medicine (SMFM) recommend that CMA as a first-line test is recommended when gen- etic analysis is performed in cases with fetal structural * Correspondence: firstname.lastname@example.org; email@example.com anomalies . For those FGR fetuses without ultrasonic Nanfang Hospital, Southern Medical University, Guangzhou 510515, structural anomaly, also defined as isolated FGR, Guangdong, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. An et al. Molecular Cytogenetics (2018) 11:33 Page 2 of 6 whether to implement CMA is still under consideration. amniocytes showed a normal 46,XY karyotype, and no In this study, we sought to investigate the genetic causes trisomy 22 or small markers were observed after of isolate FGR by SNP array and karyotype. counting 70 metaphase cells. Interphase FISH was not selected by the patient in the prenatal testing. SNP array Results showed a mosaic of trisomy 22 in the uncultured A total of 155 cases with isolate FGR met the inclusion samples, which was discordant with the normal result of criteria. 28 cases refused to accept an invasive procedure karyotype. At present, the pregnancy is still going on. and 127 cases were consented to participate in the study. The other 8 (Case 3–10) pathogenic CNV cases were 52 prenatal samples were obtained by amniocentesis and terminated with the parents’ request after the genetic 75 were obtained by cordocentesis. The clinical charac- counseling. Case 3 was revealed a four-copy fragment of teristics of pregnant women included in this study were 68 Mb in 9p24.3q13, and karyotyping demonstrated a summarized in Table1.Early-onset group and late-onset marker chromosome with 47, XX,+mar/46,XX . one were similar regarding maternal age, height, BMI Case 4 was shown a loss of 35.1 Mb of chromosome and nulliparity (Table 1). 4p16.3p15.1 overlapping the Wolf-Hirschhorn syndrome Among the 127 cases, 9.4% (12/127) chromosomal region. Case 5 was revealed a loss of 2.8 Mb of chromo- abnormalities were detected totally and the clinical some 15p11.2. The fetus was diagnosed as Prader-willi characteristic and related syndromes or phenotype syndrome because of a paternal loss confirmed by trios were listed (Table 2). Taking into accounting the diag- analysis. A loss of 3.1 Mb of chromosome 22q11.21 re- nosed gestation, the positive detected rate was 9.6% lated to DiGeorge syndrome was found in Case 6. In (5/52) in early-onset group and 9.3% (7/75) in late- Case 7,CMA revealed a loss of 1.5 Mb of chromosome onset group respectively. The difference between 7q11.23. This deletion is termed the “Willianms-Beuren early-onset group and late-onset group is no signifi- syndrome”. In Case 8 and Case 9, CMA showed patho- cant (P = 1.00). Karyotype analysis identified 4 cases genic CNVs related to delayed development and mental including 3 imbalanced genomes and 1 pericentric in- retardation according to the Decipher database. In Case version. CMA detected 10 pathogenic CNV and 2 10,CMA showed a copy neutral loss of heterozygosity VOUS case. Compared to karyotype analysis, CMA (LOH) of 19.2 Mb of chromosome 15q14q21.3.After has a 5.5% (7/127) incremental yield of pathogenic trios analysis with UPD tool, a maternal UPD(15) was chromosomal abnormalities and a 1.6% (2/127) VOUS confirmed and the fetus was diagnosed as Prader-willi detected rate. syndrome. Case 11 was confirmed a karyotype of 46, In Case 1-Case 10, there were ten pathogenetic CNVs XX, inv.(4)(p14;q28),which inherited from the pater- de novo detected by CMA with parent-offspring analysis. nity, and CMA revealed a gain of four copies of 670 In Case 1, due to an indication of isolated FGR, the pa- Kb in chromosome 5p15.31. No information was tient requested a diagnosis of CMA to get more genetic available for its pathogenesis. The parents refused to information about the fetus and reduce the waiting time. have further CMA trios testing. The clinical signifi- CMA revealed an abnormal female chromosome com- cance of this duplication is not known. Fetal death in plement, including the loss of one complete X chromo- uterus was diagnosed by ultrasound at 34 weeks. In some. This finding is consistent with 45,X. Karyotype Case 12, SNP array revealed a gain of 493 Kb of analysis of cultured amniocytes confirmed the CMA re- chromosome 22q11.21. This segment highly varied ac- sult. The fetus was delivered at 36 weeks, the birth cording to the database. The origin of the gained weights of the infant were 2300 g. In Case 2, the copy was unclear due to the parents’ decline. A male pregnant woman experienced an amniocentesis because infant was delivered with a 2300 g birth weight at NIPT indicated a high risk of trisomy 22. Cultured 37 weeksand followingupto10monthswas Table 1 Clinical characteristics of the pregnant women Group Early-onset (n = 52) Late-onset (n = 75) maternal age (years) 33.6(19.9–43.5) 32.4(20.5–41.5) height(cm) 160.1(154.5–171.5) 161.2(149.5–169.3) BMI 23.3(19.2-26.8) 24.1(18.5–27.4) Nullipara (62.4%) (65.3%) b b gestational age at diagnosis(weeks) 22.5(19.0–23.8) 28.2(24.0-32.5) BMI based on the weight and height at the visit of the first trimester; P < 0.05 An et al. Molecular Cytogenetics (2018) 11:33 Page 3 of 6 Table 2 Karyotype and SNP array abnormal results Case Gestational age Ultrasound Karyotype results SNP array results Length Inheritance Syndrome/phenotype Pregnancy NO. (weeks) findings outcome Case 1 23 None 45,X arr[hg19] Xp22.33q28(168,546–155,233,731)×1 155 Mb de novo Turner syndrome preterm birth Case 2 21 None 46,XY array[h19] WC de novo Mosaic trisomy In pregnancy (22)×2~3 22 Case 3 23 None 47,XX,+mar/ arr[hg19] 68 Mb de novo mosaic tetrasomy 9p TOP 46,XX  9p24.3q13(208,454–68,216,577) × 4 Case 4 28 Hypoplastic Nasal 46,XX,del(4)(p15) arr[hg19] 4p16.3p15.1(68,345–35,252,743) × 1 35.1 de novo Wolf-Hirschhorn TOP Bone Mb syndrome Case 5 22 None 46,XX arr[hg19] 15q11.2(22,770,421–25,626,665) × 1 2.8 Mb de novo Prader-Willi syndrome TOP Case 6 24 None 46,XY arr[hg19] 22q11.21(18,648,855–21,800,471) × 1 3.1 Mb de novo DiGeorge syndrome TOP Case 7 27 None 46,XY arr[hg19] 7q11.23(72,624,203–74,143,240) × 1 1.5 MB de novo Willianms-Beuren syndrome TOP Case 8 24 Oligohydramnios 46,XX arr[hg19] 14q32.33(104,856,497– 2.4 Mb de novo delayed development,mental TOP 107,281,980)×1,19p13.3(260,912–4,226,075)× 3 4.0 Mb retardation Case 9 22 None 46,XY arr[hg19] 3q26.33q27.2(182,374,672–185,041,523)×1 2.6 Mb de novo delayed development,mental TOP retardation +3 b Case 31 Polyhydramnios 46,XX arr[hg19] 15q14q21.3(35,077,111–54,347,324) hmz 19.2 Mb de novo Prader-Willi syndrome TOP Case 24 Tricuspid 46,XX, arr[hg19] 5p15.31(6,752,756–7,429,552) × 4 670 Kb unknown VOUS Intrauterine 11 Regurgitation inv.(4)(p14;q28)pat death Case 25 Echogenic 46,XY arr[hg19] 493 Kb unknown VOUS Term birth 12 intracardiac 22q11.21(18,5 focus 12,066–19,00 4772)×3 TOP termination of pregnancy, WC whole chromosome, VOUS variant of uncertain significance the detected sample was uncultured amniocyte a maternal UPD(15) was diagnosed by UPD tool An et al. Molecular Cytogenetics (2018) 11:33 Page 4 of 6 normal. The rest cases with negative results had no growth . A maternal uniparental disomy (mUPD) in identifiable phenotype at birth. which two copies of chromosome 15 of maternal origin accounts for 20–25% of Prader-Willi syndrome (PWS) Discussion . A study from the UK supports that the changing Several organizations recommend that CMA should be genetic subtype proportions of PWS are due to an in- applied to detect genetic abnormalities in fetus with crease in the numbers of mUPD babies because of the structural anomalies. Significant fetal growth restriction increasing proportions of older mothers . The inci- is often seen with trisomy 13 and trisomy 18, which are dence of UPD is estimated to be approximately 1:3500 usually confirmed multiple malformations by ultrasound. live births and growing numbers of patients will be de- But, it is ambiguous that whether a pregnant woman tected with the advent of the whole-genome techniques should accepted the invasive prenatal procedures when a . As in Case 10, a 41-year-old woman accepted cor- FGR is diagnosed with a normal ultrasound scanning. In docentesis procedure with Indication of isolated FGR this study, we determined the incidence and patterns of and decreased fetal movement at 31 weeks of chromosomal abnormalities in a cohort of 127 FGR gestation. Finally, a UPD(15)mat has been confirmed by without structural anomalies. The overall detection rate trios analysis with UPD tool , and the fetus was of chromosomal abnormalities were 9.4% (12/127).We diagnosed with PWS. So UPD should deserve more explored the genetic abnormalities of FGR diagnosed at attention in FGR cases especially with advanced-aged different gestational ages, However, there was no statis- pregnant women. tical difference between the early-onset group and late- In the prenatal setting, it may be difficult to interpret onset one (9.6% vs. 9.3%, P = 1.00).The reason may due the significance of a CNV due to the limitations of fetal to limited sample size. We still recommended that it was imaging and the limited information currently available reasonable to discuss the probability of an invasive pre- correlating prenatal CNV findings with postnatal pheno- natal procedure with pregnant woman in case of isolate type . VOUS may cause considerable stress and anx- FGR diagnosed before 33 weeks. Although Merel recom- iety as the parents may not obtain a satisfied mends that testing for chromosomal anomalies should expectation. The parents refused to have further testing. be offered in case of FGR between 18 and 24 weeks ges- Case 11 exhibited a chromosome complement with the tation . gain of 670 Kb in chromosome 5p15.31 involved two Frequently, FGR is a major and only manifestation in genes: PAPD7 and ADCY2. Four copies were detected the prenatal diagnosis of some micro-duplication/dele- and the breakpoints occurred in PAPD7 and ADCY2 re- tion syndromes, and intellect disability or delayed devel- spectively, revealed by CMA. So far, both of the genes opment was solely clinical presentation after birth. Due whether cause disorders has not been reported. Parental to the limited resolution of karyotype analysis, many DNA was not available for further analysis and the fetus well-characterized disease-causing genetic variants could died in uterus at 34 weeks. We were unable to deter- not be detected. This study demonstrated 5 pathogenic mine whether the duplication had occurred de novo. CNV de novo (Case5–9), which only detected by CMA, Similarly, a VOUS was defined in Case 12. Finally, the because the genetically material imbalance was less than VOUS detected rate was 1.6%, similar to the literature 5 Mb in length. After genetic diagnosis, each case was . re-evaluated by ultrasound. Just like in Case 6, DiGeorge CMA does not provide information about the chromo- syndrome was found by CMA in the isolated FGR fetus somal mechanism of a genetic imbalance. For example, and confirmed by FISH. Common ultrasound anomalies the fetus of Case 8 was diagnosed as mosaic tetrasomy included palatal anomalies, cardiovascular anomalies 9p with the combination of CMA and karyotype ana- and scoliosis  were easy to confirm, however, this lysis. The components of the prenatal sample would case was just an isolated FGR without any structural change following the culture process, which increased anomaly. At 27 weeks, a smaller thymus gland was con- the uncertainty of diagnosis results. In Case 2, the result firmed by Ultrasound before termination of pregnancy of CMA indicated a mosaic of trisomy 22 and the karyo- with the parent’s request. type was normal. Maybe, the direct detection of uncul- Uniparental disomy (UPD) is another genetic cause of tured samples by CMA can more fully represent the FGR. The concept of UPD was first introduced by Eric genetic characteristics of the fetus.The ACOG and Engel, owing to the fact that both members of such a SMFM recommend that providers discuss the benefits pair of chromosomes from only one parent . The and limitations of CMA and conventional karyotype pathogenesis of UPD is determined by both epigenetic with patients, and that both options are available to imprinting as well as demasking of autosomal-recessive women who choose to undergo prenatal diagnostic test- diseases (homozygosity by isodisomy). It is striking that ing . QF-PCR or FISH analysis would be an alterna- many UPDs are associated with disturbed intrauterine tive in the rapid prenatal test for trisomy 13, 18, 21and An et al. Molecular Cytogenetics (2018) 11:33 Page 5 of 6 sex chromosome aneuploidies. But CMA could detect substance use and abuse were excluded. All the micro-deletion/duplication with a high-resolution view morphology scan were performed by experienced of the whole genome and copy neutral LOH with plat- operators according to the practice guidelines for forms incorporating SNP probes. More pregnant women performance of the routine fetal ultrasonic scan released are willing to choose CMA in the prenatal setting. by the International Society of Ultrasound in Obstetrics Inevitably, a limitation of the prospective study is that and Gynecology(ISUOG). Based on the gestational age the postnatal follow-up is still pending, in order to ac- at diagnosis, the cases were divided into two groups: quire the long-term growth and development aspects of early-onset group (< 24 weeks) and late-onset group born cases. How to select a proper criterion to define (24–33 weeks). All women received pre-test counseling FGR is another puzzle . The ultrasound limit for regarding the procedure-related risks and benefits from FGR is fetal weight (EFW) or abdominal circumference karyotype and microarray. Women with positive results (AC) under the 3rd, 5th, 10th percentile or below 2 were offered fully counseling by the fetal medicine spe- Standard Deviation (SD) from the population standard cialists. All the prenatal samples obtained by amniocen- or reference . We choose the 10th percentile as a tesis or cordocentesis were processed in parallel using cut-off to avoid omitting the so-called “mildly growth re- both SNP array and G-banding for conventional stricted” which are at increased risk for complications karyotyping. between the 3th and 10th percentile . This fact may result in a selection bias leading to underestimated in- Karyotype analysis cremental yield of CMA. Amniotic Fluid or fetal cord blood samples were ob- tained according to the prenatal procedure protocol Conclusion . The cultured amniocytes or lymphocytes were ana- In summary, as underlying factors in case of FGR, aneu- lyzed by routine cytogenetic analysis using G-banding ploidy, submicroscopic abnormality and UPD should be techniques at a resolution of 400–500 bands. The num- considered comprehensively. An invasive prenatal pro- ber of cells examined varied between 20 and 30.The re- cedure is strongly recommended when FGR is diagnosed sults of cultured amniocytes are available within 14 to before 33 weeks. CMA detected all the chromosomal ab- 20 days and the ones of lymphocytes within 5 to 7 days. erration detected by karyotyping, and has a 5.5% (7/127) incremental detection rate of genetic cause of isolated FGR, which could impact the clinical decision. CMA as SNP array and data interpretation the first-line test plus karyotyping is effective and feas- A CytoScan 750 K array (Affymetrix Inc., Santa Clara, ible as a joined prenatal testing for suspected FGR cases. CA, USA) was used for assessing the prenatal samples, which covered over 750,000 markers distributed across Methods the entire human genome, including 200,000 probes for Ethics and cases selection single nucleotide polymorphisms (SNPs) and 550,000 The study was approved by the ethics review boards probes for copy number variations (CNVs). of Nanfang Hospital (No.NFEC-2016-093) and Fujian Hybridization, data extraction and analysis were per- Provincial Maternity and Children’sHospital(No.12). formed as per the manufacturer’s protocol. A resolution Written informed consent was obtained in all cases. was generally applied: gains or losses ≥400 kb and loss This prospective multi-centers cohort study consisted of heterozygosity (LOH) ≥ 10 Mb . The results were of singleton FGR cases underwent invasive prenatal analyzed with Chromosome Analysis Suite (ChAS) soft- diagnostic testing at Fujian Provincial Maternity and ware (Affymetrix, USA), using annotations of the gen- Children’s Hospital (FPMCH) and Nanfang Hospital ome version GRCH37 (hg19). The Database of Genomic (NFH) of Southern Medical University from July 2015 to Variants (DGV), the Database of Chromosome Imbal- February 2018. These two hospitals are tertiary referral ance and Phenotype in Humans Using Ensemble Re- prenatal diagnosis center in each province. Gestational sources (DECIPHER), the International Standards for age (GA) was assessed according to last menstrual Cytogenomic Arrays Consortium (ISCA), OMIM genes period (LMP) and crown-rump length (CRL) at 11 to and the local database were used to evaluate the CNVs 13 weeks. Inclusion criteria was FGR without identified in this study. The CNVs were classified as structural anomalies diagnosed by ultrasound when the benign, pathogenic, or variants of uncertain signifi- EFW is less than the 10th percentile for gestational age cance(VOUS) according to the American College of based on the formula of Hadlock C . At high risk of Medical Genetics (ACMG) guideline . Blood sam- noninvasive prenatal testing for trisomy 13, 18 and 21, ples were collected from both parents and were ana- multiple gestation, chronic nephropathy, preeclampsia, lyzed if variants of uncertain significance (VOUS) antiphospholipid syndrome, TORCH infection, were detected in the fetal sample by CMA. An et al. Molecular Cytogenetics (2018) 11:33 Page 6 of 6 Statistical analysis 8. Dugoff L, Norton ME, Kuller JA. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215(4):B2–9. 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Published: Jun 4, 2018