Abnormal Copy Number Variations Research Articles

The use of high-resolution SNP arrays to detect congenital cardiac defects

Objective Copy number variations (CNVs) detected by high-resolution single nucleotide polymorphism microarrays (SNP arrays) have been associated with congenital heart defects (CHDs). The genetic mechanism underlying the development of CHDs remains unclear. Methods High-resolution SNP arrays were used to detect CNVs and traditional chromosomal analyses, respectively, were carried out on 60 and 249 fetuses from gestational 12–37 weeks old, having isolated or complex CHDs that were diagnosed using prenatal ultrasound. Results Twenty of the 60 fetuses (33.5%) had abnormalities, of which 23 CNVs (12 pathogenic, five probable pathogenic and six of undetermined significance) were detected by SNP arrays, and two distinct CNVs were present in three of these fetuses. In addition, in 39 patients with isolated congenital heart disease who had normal karyotypes, abnormal CNVs were present in 28.2% (11/39), and in patients with complex coronary artery disease, 19.0% (4/21) had abnormal karyotypes and 42.9% (9/21) had abnormal CNVs. In patients with complex coronary artery disease, 19.0% (4/21) had abnormal karyotypes and 42.9% (9/21) had abnormal CNVs. Conclusions In conclusion, genome-wide high-resolution SNP array can improve the diagnostic rate and uncover additional pathogenic CNVs. The submicroscopic deletions and duplications of Online Mendelian Inheritance in Man (OMIM) genes found in this study have haploinsufficient (deletion) or triplosensitive (duplication) traits, which further clarify the etiology and inheritance of CHDs.

Pathogenic copy number variations are associated with foetal short femur length in a tertiary referral centre study.

Shortened foetal femur length (FL) is a common abnormal phenotype that often causes anxiety in pregnant women, and standard clinical treatments remain unavailable. We investigated the clinical characteristics, genetic aetiology and obstetric pregnancy outcomes of foetuses with short FL and provided a reference for perinatal management of such cases. Chromosomal microarray analysis was used to analyse the copy number variations (CNV) in short FL foetuses. Of the 218 foetuses with short FL, 33 foetuses exhibited abnormal CNVs, including 19 with pathogenic CNVs and 14 with variations of uncertain clinical significance. Of the 19 foetuses with pathogenic CNVs, four had aneuploidy, 14 had deletions/duplications, and one had pathogenic uniparental diploidy. The 7q11.23 microdeletion was detected in three foetuses. The severity of short FL was not associated with the rate of pathogenic CNVs. The duration of short FL for the intrauterine ultrasound phenotype in foetuses carrying a pathogenic CNV was independent of the gestational age. Further, maternal age was not associated with the incidence of foetal pathogenic CNVs. Adverse pregnancy outcomes occurred in 77 cases, including termination of pregnancy in 63 cases, postnatal dwarfed foetuses with intellectual disability in 11 cases, and three deaths within 3 months of birth. Pathogenic CNVs closely related to foetal short FL were identified, among which the 7q11.23 microdeletion was highly associated with short FL development. This study provides a reference for the perinatal management of foetuses with short FL.

Advanced maternal age: copy number variations and pregnancy outcomes.

Objective: Adverse pregnancy outcomes are closely related to advanced maternal age (AMA; age at pregnancy ≥35years). Little research has been reported on aneuploid abnormalities and pathogenic copy number variations (CNVs) affecting pregnancy outcomes in women with AMA. The purpose of this study was to assess CNVs associated with AMA in prenatal diagnosis to determine the characteristics of pathogenic CNVs and assist with genetic counseling of women with AMA. Methods: Among 277 fetuses of women with AMA, 218 (78.7%) were isolated AMA fetuses and 59 (21.3%) were non-isolated AMA fetuses and showed ultrasound anomalies from January 2021 to October 2022. Isolated AMA was defined as AMA cases without sonographic abnormalities. Non-isolated AMA was defined as AMA cases with sonographic abnormalities such as sonographic soft markers, widening of the lateral ventricles, or extracardiac structural anomalies. The amniotic fluid cells underwent routine karyotyping followed by single nucleotide polymorphism array (SNP-array) analysis. Results: Of the 277 AMA cases, karyotype analysis identified 20 chromosomal abnormalities. As well as 12 cases of chromosomal abnormalities corresponded to routine karyotyping, the SNP array identified an additional 14 cases of CNVs with normal karyotyping results. There were five pathogenetic CNVs, seven variations of uncertain clinical significance (VOUS), and two benign CNVs. The detection rate of abnormal CNVs in non-isolated AMA cases was increasing (13/59; 22%) than in isolated AMA cases (13/218; 5.96%) (p < 0.001). We also determined that pathogenic CNVs affected the rate of pregnancy termination in women with AMA. Conclusion: Aneuploid abnormalities and pathogenic CNVs affect pregnancy outcomes in women with AMA. SNP array had a higher detection rate of genetic variation than did karyotyping and is an important supplement to karyotype analysis, which enables better informed clinical consultation and clinical decision-making.

The Evaluation of Genetic Diagnosis on High-Risk Fetal CAKUT.

Background: It is challenging to make an accurate prenatal diagnosis for congenital anomalies of the kidney and urinary tract (CAKUT) because of its pathologic diversity. This study aims to evaluate the performance of whole-exome sequencing (WES) combined with karyotype analysis and copy number variations (CNVs) in diagnosing high-risk fetal CAKUT. Methods: We conducted a retrospective study on prenatal diagnoses of CAKUT in our hospital from January 2020 to April 2021. The research studied 24 high-risk fetuses with CAKUT who were scanned by ultrasonography at the prenatal diagnosis center of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. The likely pathogenic gene variants were screened for the patients and their parents by multiple approaches, including karyotype analysis, CNVs and WES, and further verified with Sanger sequencing. Results: ①We detected abnormal CNVs in 20.8% (5/24) of the fetuses but only 8.3% (2/24) fetuses had abnormal karyotypes. ②Of the 15 CAKUT fetuses, positive findings (40%) were detected by WES. Of the 9 high-risk fetuses with CAKUT (negative findings in ultrasound scan but with family history), we found abnormal variants (77.8%) through WES. Conclusion: The application of CNVs and WES showed advance in prenatal diagnosis of CAKUT and the pathogenic gene variants were detectable especially for high-risk fetuses with negative ultrasound findings on CAKUT in the preliminary study. The applied strategy could be used to improve the accuracy of prenatal diagnosis for CAKUT in the future.

Classifying and Evaluating Fetuses With Ventriculomegaly in Genetic Etiologic Studies.

The association between genetics and fetuses with ventriculomegaly (VM) is unknown. This study aimed to classify and evaluate abnormal copy number variations (CNVs) in fetuses with VM. From December 2016 to September 2020, amniotic fluid or umbilical cord blood from 293 pregnant women carrying fetuses with VM was extracted for single-nucleotide polymorphism microarray (SNP array). Among 293 fetuses with VM, 31 were detected with abnormal CNVs, including 22 with pathogenic CNVs (7.51%) and nine with variation of uncertain clinical significance (VUS) CNVs (3.07%). Of the 22 fetuses with pathogenic CNVs, 13 had known disease syndromes. Among the 293 fetuses, 133 had mild isolated VM [pathogenic CNVs, 7/133 (5.26%)]; 142 had mild non-isolated VM [pathogenic CNVs, 13/142 (9.15%)]; 12 had severe isolated VM [pathogenic CNVs, 2/12 (16.67%)]; and six had severe non-isolated VM (no abnormal CNVs was detected). There was no statistical significance in the rate of pathogenic CNVs among the four groups (P = 0.326, P > 0.05). Among the 267 fetuses with successful follow-up, 38 were terminated (of these, 21 had pathogenic CNVs). Of the 229 fetuses, two had developmental delay and the remaining 227 had a good prognosis after birth. Overall, the results are useful for the detection of fetal microdeletion/microduplication syndrome and for the accurate assessment of fetal prognosis in prenatal consultation.

Choroid Plexus Cysts: Single Nucleotide Polymorphism Array Analysis of Associated Genetic Anomalies and Resulting Obstetrical Outcomes.

ObjectiveChoroid plexus cysts (CPC) are pseudocysts in the fetal choroid plexus and can be detected during ultrasound examination. However, the etiology of fetuses with CPC is still unknown. This study aimed to evaluate the genetic anomalies of fetuses with CPC using single nucleotide polymorphism (SNP) array analysis, as well as their obstetrical outcomes.Patients and MethodsAmong 201 fetuses, 108, 69, and 24 had isolated CPC (iCPC), CPC with sonographic soft markers, and CPC with sonographic structural malformations, respectively. All fetuses underwent conventional karyotyping analysis and SNP array analysis.ResultsAmong 201 fetuses with CPC, 15 had chromosomal abnormalities (7.5%, 15/201), including nine fetuses with trisomy 18. Further, SNP array results were consistent with the conventional karyotype analysis and additionally revealed 6.0% (12/201) abnormal copy number variations (CNVs). The rates of pathogenic CNVs in fetuses with iCPC, CPC combined with sonographic soft markers, and CPC combined with sonographic structural malformations were 6.5%, 6.0%, and 45.8%, respectively, with significant differences among the groups.ConclusionThe results of the SNP array affected the obstetrical outcomes. CPC is thus associated with pathogenic CNVs in approximately 10.9% of cases. Therefore, SNP array should be offered for prenatal testing of fetuses with CPC.

Clinical Utility and the Yield of Single Nucleotide Polymorphism Array in Prenatal Diagnosis of Fetal Central Nervous System Abnormalities.

Applying single nucleotide polymorphism (SNP) array to identify the etiology of fetal central nervous system (CNS) abnormality, and exploring its association with chromosomal abnormalities, copy number variations, and obstetrical outcome. 535 fetuses with CNS abnormalities were analyzed using karyotype analysis and SNP array. Among the 535 fetuses with CNS abnormalities, chromosomal abnormalities were detected in 36 (6.7%) of the fetuses, which were consistent with karyotype analysis. Further, additional 41 fetuses with abnormal copy number variations (CNVs) were detected using SNP array (the detection rate of additional abnormal CNVs was 7.7%). The rate of chromosomal abnormalities, but not that of pathogenic CNVs in CNS abnormalities with other ultrasound abnormalities was significantly higher than that in isolated CNS abnormalities. The rates of chromosomal abnormalities and pathogenic CNVs in fetuses with spine malformation (50%), encephalocele (50%), subependymal cyst (20%), and microcephaly (16.7%) were higher than those with other isolated CNS abnormalities. The pregnancies for 36 cases with chromosomal abnormalities, 18 cases with pathogenic CNVs, and three cases with VUS CNVs were terminated. SNP array should be used in the prenatal diagnosis of fetuses with CNS abnormalities, which can enable better prenatal assessment and genetic counseling, and affect obstetrical outcomes.

Copy Number Variant Detection with Low-Coverage Whole-Genome Sequencing Represents a Viable Alternative to the Conventional Array-CGH.

Copy number variations (CNVs) represent a type of structural variant involving alterations in the number of copies of specific regions of DNA that can either be deleted or duplicated. CNVs contribute substantially to normal population variability, however, abnormal CNVs cause numerous genetic disorders. At present, several methods for CNV detection are applied, ranging from the conventional cytogenetic analysis, through microarray-based methods (aCGH), to next-generation sequencing (NGS). In this paper, we present GenomeScreen, an NGS-based CNV detection method for low-coverage, whole-genome sequencing. We determined the theoretical limits of its accuracy and obtained confirmation in an extensive in silico study and in real patient samples with known genotypes. In theory, at least 6 M uniquely mapped reads are required to detect a CNV with the length of 100 kilobases (kb) or more with high confidence (Z-score > 7). In practice, the in silico analysis required at least 8 M to obtain >99% accuracy (for 100 kb deviations). We compared GenomeScreen with one of the currently used aCGH methods in diagnostic laboratories, which has mean resolution of 200 kb. GenomeScreen and aCGH both detected 59 deviations, while GenomeScreen furthermore detected 134 other (usually) smaller variations. When compared to aCGH, overall performance of the proposed GenemoScreen tool is comparable or superior in terms of accuracy, turn-around time, and cost-effectiveness, thus providing reasonable benefits, particularly in a prenatal diagnosis setting.

Chromosomal Microarray Analysis for the Prenatal Diagnosis in Fetuses with Nasal Bone Hypoplasia: A Retrospective Cohort Study.

BackgroundPrevious studies have shown a strong correlation between fetal nasal bone hypoplasia and chromosomal anomaly; however, there is little knowledge on the associations of fetal nasal bone hypoplasia with chromosomal microdeletions and microduplications until now. Chromosomal microarray analysis (CMA) is a high-resolution molecular genetic tool that is effective to detect submicroscopic anomalies including chromosomal microdeletions and microduplications that cannot be detected by karyotyping. This study aimed to examine the performance of CMA for the prenatal diagnosis of nasal bone hypoplasia in the second and third trimesters.Subjects and MethodsA total of 84 pregnant women in the second and third trimesters with fetal nasal bone hypoplasia, as revealed by ultrasound examinations, were enrolled, and all women underwent karyotyping and CMA with the Affymetrix CytoScan 750K GeneChip Platform. The subjects included 32 cases with fetal nasal bone hypoplasia alone and 52 cases with fetal nasal bone hypoplasia combined with other ultrasound abnormalities, and the prevalence of genomic abnormality was compared between these two groups.ResultsKaryotyping detected 21 cases of chromosomal anomaly in the 84 study subjects (21/84, 25%), including trisomy 21 (14 cases), trisomy 18 (3 cases), 46, del (4)(p16) karyotype (2 cases), 47, XYY syndrome (1 case) and 46, XY, del (5) (p15) karyotype (1 case). CMA detected additional four fetuses with pathogenic copy number variations (CNVs) and six fetuses with uncertain clinical significance (VOUS). No significant difference was detected in the prevalence of genomic abnormality in fetuses with nasal bone hypoplasia alone and in combination with other ultrasound abnormalities (13/32 vs 18/52; χ2 = 0.31, P > 0.05). The pregnancy was terminated in 21 fetuses detected with chromosomal abnormality and 4 fetuses detected with pathogenic CNVs. Among the other six fetuses detected with VOUS, the parents chose to continue the pregnancy, and the newborns all had normal clinical phenotypes.ConclusionIn addition to chromosomal abnormalities identified in 21 fetuses by karyotyping, CMA detected additional 10 fetuses with abnormal CNVs (10/84, 11.9%) in the study population. CMA is a promising powerful tool for prenatal diagnosis that may provide valuable data for the accurate assessment of fetal prognosis and the decision of pregnancy continuation during the prenatal clinical counseling.

Performance of Chromosomal Microarray Analysis for Detection of Copy Number Variations in Fetal Echogenic Bowel.

BackgroundFetal echogenic bowel (FEB) is associated with an increased risk of poor pregnant outcomes; however, karyotyping fails to detect copy number variations (CNVs) in FEB. This study aimed to evaluate the performance of chromosomal microarray analysis (CMA) for detection of FEB.MethodsThe medical records of 147 pregnant women with FEB recruited during December 2015 to December 2018 were retrospectively reviewed, and prenatal samples were collected for karyotyping and CMA. The detection of chromosomal abnormality was compared between karyotyping and CMA.ResultsKaryotyping identified eight cases with abnormal karyotypes (5.44% prevalence), including four fetuses with pathogenic aneuploidy, three with chromosome polymorphism and one with balanced chromosome translocation. CMA identified 13 abnormal CNVs (8.84% prevalence), including 4 fetuses with pathogenic aneuploidy as detected by karyotyping and 9 additional CNVs with normal karyotypes; however, CMA failed to detect chromosome polymorphism and balanced chromosome translocation. In fetuses with isolated FEB, no cases presented pathogenic findings and CMA detected two cases with variants of uncertain significance (VOUS). In cases presenting FEB along with other ultrasound abnormalities, CMA detected three cases with pathogenic CNVs and four cases with VOUS in addition to four cases with aneuploidy. There was no significant difference in the detection of abnormal CNVs between the fetuses with echogenic bowel alone and along with other ultrasound abnormalities (10% vs 8.67%, P > 0.05). Except 9 fetuses lost to the follow-up, the other 138 fetuses with echogenic bowel were successfully followed up. Pregnancy was terminated in 5 fetuses with chromosomal abnormality, 2 with pathogenic CNVs and 1 with VOUS, and other 16 with normal karyotypes and CMA findings but showing ultrasound abnormalities or multiple malformations.ConclusionIsolated FEB is associated with a good prognosis, and a satisfactory pregnant outcome is expected for fetuses with echogenic bowel that are negative for chromosomal anomalies and other severe structure abnormalities. CMA shows an important value in the genetic diagnosis of FEB. As a supplement to karyotyping, CMA may improve the accuracy of prenatal diagnosis of fetal intestinal malformations in pregnant women with FEB.

Evaluation of chromosomal abnormalities and copy number variations in fetuses with ultrasonic soft markers

BackgroundSome ultrasonic soft markers can be found during ultrasound examination. However, the etiology of the fetuses with ultrasonic soft markers is still unknown. This study aimed to evaluate the genetic etiology and clinical value of chromosomal abnormalities and copy number variations (CNVs) in fetuses with ultrasonic soft markers.MethodsAmong 1131 fetuses, 729 had single ultrasonic soft marker, 322 had two ultrasonic soft markers, and 80 had three or more ultrasonic soft markers. All fetuses underwent conventional karyotyping, followed by single nucleotide polymorphism (SNP) array analysis.ResultsAmong 1131 fetuses with ultrasonic soft markers, 46 had chromosomal abnormalities. In addition to the 46 fetuses with chromosomal abnormalities consistent with the results of the karyotyping analysis, the SNP array identified additional 6.1% (69/1131) abnormal CNVs. The rate of abnormal CNVs in fetuses with ultrasonic soft marker, two ultrasonic soft markers, three or more ultrasonic soft markers were 6.2%, 6.2%, and 5.0%, respectively. No significant difference was found in the rate of abnormal CNVs among the groups.ConclusionsGenetic abnormalities affect obstetrical outcomes. The SNP array can fully complement conventional karyotyping in fetuses with ultrasonic soft markers, improve detection rate of chromosomal abnormalities, and affect pregnancy outcomes.

SNP Array as a Tool for Prenatal Diagnosis of Congenital Heart Disease Screened by Echocardiography: Implications for Precision Assessment of Fetal Prognosis.

ObjectiveThis study aimed to examine the effectiveness of the SNP array for the prenatal diagnosis of congenital heart disease (CHD) screened by echocardiography.Patients and MethodsA total of 356 pregnant women with fetal congenital heart malformations revealed by echocardiography at the Center for Prenatal Diagnosis of Fujian Maternal and Children Hospital during the period from November 2016 through July 2019 were recruited. The fetuses were assigned into three cohorts, including 142 with a single cardiac malformation, 106 with multiple cardiac malformations and 108 with cardiac and extracardiac malformations. All fetuses underwent chromosomal karyotyping and SNP array simultaneously, and the effectiveness of the SNP array for the prenatal diagnosis of CHD was evaluated.ResultsThe overall prevalence of abnormal karyotypes was 9.3% among the 356 fetuses with CHD, and a higher proportion was found in fetuses with cardiac and extracardiac malformations (18.5%) than in those with single (5.6%) or multiple cardiac malformations (4.7%) (P<0.05). Consistent with karyotype analysis, SNP array detected an additional 25 fetuses with pathogenic copy number variations (CNVs), seven with variant of unknown significance (VOUS) and seven with benign CNVs, and a lower proportion of abnormal CNV was found in fetuses with a single cardiac malformation (4.2%) than in those with multiple cardiac malformations (9.4%) or cardiac and extracardiac malformations (14.8%) (P<0.05). Among the 33 fetuses with chromosomal abnormality, postnatal follow-up showed termination of pregnancy in 25 with pathogenic CNVs, one with VOUS, and six with normal karyotypes and SNP array findings but severe multiple malformations by ultrasonography.ConclusionSNP array increases the overall detection of abnormal CNVs by 9%, which improves the detection of CNVs associated with CHD. SNP array may serve as a tool for prenatal diagnosis of CHD that facilitates the discovery of pathogenic genes associated with CHD and provide valuable insights into the precision assessment of fetal prognosis during the prenatal counseling.

Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes

Many fetuses are found to have ultrasonic abnormalities in the late pregnancy. The association of fetal ultrasound abnormalities in late pregnancy with copy number variations (CNVs) is unclear. We attempted to explore the relationship between types of ultrasonically abnormal late pregnancy fetuses and CNVs. Fetuses (n = 713) with ultrasound-detected abnormalities in late pregnancy and normal karyotypes were analyzed. Of these, 237 showed fetal sonographic structural malformations and 476 showed fetal non-structural abnormalities. Single nucleotide polymorphism (SNP)-based chromosomal microarray (CMA) was performed on the Affymetrix CytoScan HD platform. Using the SNP array, abnormal CNVs were detected in 8.0% (57/713) of the cases, with pathogenic CNVs in 32 cases and variants of uncertain clinical significance (VUS) in 25 cases. The detection rate of abnormal CNVs in fetuses with sonographic structural malformations (12.7%, 30/237) was significantly higher (P = 0.001) than that in the fetuses with non-structural abnormalities (5.7%, 27/476). Overall, we observed that when fetal sonographic structural malformations or non-structural abnormalities occurred in the third trimester of pregnancy, the use of SNP analysis could improve the accuracy of prenatal diagnosis and reduce the rate of pregnancy termination.

Evaluation of chromosomal abnormalities and copy number variations in late trimester pregnancy using cordocentesis.

Because the numbers of detected fetal abnormalities increase as gestation progresses, we evaluated the safety and efficacy of cordocentesis for single nucleotide polymorphism (SNP) analysis tests in 754 women during third trimester pregnancy. Conventional karyotyping was performed on all fetuses, and Affymetrix CytoScan HD was used for SNP-array testing. In addition to the 24 cases with chromosomal abnormalities detected with conventional karyotyping analysis, the SNP-array test identified 56 (7.4%) cases with normal karyotypes but abnormal copy number variations (CNVs). Of those, 24 were pathogenic CNVs and 32 were of uncertain clinical significance. In 742 of the cases, there were abnormal sonographic findings, and cytogenetic abnormalities were detected in 76 cases (10.2%). The largest number of abnormalities involved multiple malformations (21.7%), followed by defects in the lymphatics or effusion (19.0%) or urogenital system (15.3%). The use of SNP-array test fully complemented chromosome karyotype analysis after late cordocentesis. It also improved the detection rate for fetal chromosomal abnormalities and was effective for preventing and controlling the occurrence of birth defects.

Copy number variations associated with fetal congenital kidney malformations

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) constitute 20–30% of all congenital malformations. Within the CAKUT phenotypic spectrum, renal hypodysplasia (RHD) is particularly severe. This study aimed to evaluate the applicability of single-nucleotide polymorphism (SNP) array test in prenatal diagnosis of RHD for improving prenatal genetic counseling and to search for evidence of a possible causative role of copy-number variations (CNVs) in RHD.ResultsWe performed a systematic survey of CNV burden in 120 fetuses with RHD: 103 cases were isolated RHD and 17 were non-isolated RHD. Single-nucleotide polymorphism (SNP) array test was performed using the Affymetrix CytoScan HD platform. All annotated CNVs were validated by fluorescence in situ hybridization. We identified abnormal CNVs in 15 (12.5%) cases of RHD; of these CNVs, 11 were pathogenic and 4 were variants of uncertain significance. The detection rate of abnormal CNVs in non-isolated RHD was higher (29.4%, 5/17) than that in isolated RHD (9.7%, 10/103) (P = 0.060). Parents are more inclined to terminate the pregnancy if the fetuses have pathogenic results of the SNP-array test.ConclusionsThe variable phenotypes that abnormal CNVs may cause indicate the genetic counseling is needed for RHD cases.

Detection of copy number disorders associated with congenital anomalies of the kidney and urinary tract in fetuses via single nucleotide polymorphism arrays.

BackgroundWhile congenital anomalies of the kidney and urinary tract (CAKUT) constitute one‐third of all congenital malformations, the mechanisms underlying their development are poorly understood. Some studies have reported an association between CAKUT and copy number variations (CNVs) in children and adults, but few have focused on chromosomal microarray analysis (CMA) findings in fetuses with CAKUT. Therefore, we aimed to perform a CMA on fetuses with CAKUT and normal karyotypes in the presence and absence of other structural anomalies.MethodThe study was conducted in 147 fetuses with CAKUT and normal karyotypes between January 2016 and January 2019 in the Fujian Provincial Maternal and Child Health Hospital. Single nucleotide polymorphism (SNP) analysis was performed using the Affymetrix CytoScan HD platform.ResultsThe SNP array identified abnormal CNVs in 13 cases (8.8%): Six were pathogenic, and seven were variations of uncertain clinical significance (VOUS). The detection rate of abnormal CNVs in non‐isolated CAKUT was higher than that in isolated CAKUT (22.7% vs 6.4%, P = .038). Within the abnormal CNV groups, the highest frequency of CNVs was identified in fetuses with polycystic kidney dysplasia (13.5%), followed by those with renal agenesis (10.5%).ConclusionSNP array is effective for identifying chromosomal abnormalities in CNVs in fetuses with CAKUT and normal karyotypes, and help counseling.

Influence of validating the parental origin on the clinical interpretation of fetal copy number variations in 141 core family cases.

BackgroundThe sources and variants types of the copy number variations (CNVs) in prenatal fetal, and the critical role of parental origin on the interpretation of fetal CNVs are unclear.MethodsOne hundred and forty‐one prenatal core families with abnormal CNVs were selected and performed by low‐coverage massively parallel CNV sequencing (CNV‐seq).ResultsThe data showed that 72.3% of fetal CNVs were derived from parents, and 27.7% were new variations. Sixty‐three cases were heterozygous deletion, 70 cases were threefold duplication, six cases were complex deletion and duplication, and two cases were fourfold repeats. That means the rate of heterozygous deletion and duplication was approximate one. In addition, in parental‐derived fetal abnormal CNVs reports, before validating parental origin, 62 CNVs were variants of uncertain significance (VUS), 15 CNVs were likely benign, 20 CNVs were likely pathogenic, and 5 CNVs were pathogenic. However, after validating parental origin, the total clinical significance changed into 12 VUS, 89 likely benign, 1 likely pathogenic, and 0 pathogenic. The clinical interpretation of 78.4% fetal CNVs was changed and tended to be benign after parental CNVs were detected. Besides, we followed up all families. 93.3% parental‐derived fetal and 30.3% fetus in new mutation group were born healthy.ConclusionParental origin verification has an important significance for interpretation on the clinical significance of fetal CNVs.

Fetal congenital heart disease: Associated anomalies, identification of genetic anomalies by single-nucleotide polymorphism array analysis, and postnatal outcome.

Background:Congenital heart disease (CHD) is one of the most common birth defects; however, the mechanisms underlying its development are poorly understood. Recently, heritable genetic factors, including copy number variations (CNVs) and single nucleotide polymorphisms (SNPs), have been implicated in its etiology. The aim of this study was to investigate the utility of a SNP array for the prenatal diagnosis of CHD and the improvement of prenatal genetic counseling and to compare this approach to traditional chromosome analysis.Methods:One hundred and fortysix cases of CHD detected by prenatal echocardiography were analyzed. Of these, 110 were isolated CHD and 36 were of CHD with extracardiac defects. SNP analysis was performed using the Affymetrix CytoScan HD platform, which was followed by karyotype analysis. All annotated CNVs were validated by fluorescence in situ hybridization.Results:Karyotype analysis identified chromosomal abnormalities in 19 of 146 cases. In addition to the 15 chromosomal abnormalities that were consistent with the results of karyotype analysis, the SNP array identified abnormal CNVs in an additional 15.2% (22/145) cases; of these, 15 were pathogenic CNVs, three were variations of uncertain clinical significance, and four were benign CNVs. The rates at which the SNP array detected pathogenic CNVs differed significantly between cases of isolated CHD and CHD with extracardiac defects (13.6% vs. 72.2%, P = .001). The results of the SNP array also affected the rate of pregnancy termination.Conclusion:Combining SNP array with cytogenetic analyses is particularly effective for identifying chromosomal abnormalities in CNVs in fetuses with CHD, which also affects obstetrical outcomes.

Chromosomal abnormalities and copy number variations in fetal ventricular septal defects

BackgroundThis study aimed to evaluate the applicability of chromosomal microarray analysis (CMA), rather than traditional chromosome analysis, in prenatal diagnosis of ventricular septal defects (VSDs) for superior prenatal genetic counseling and to reveal a potential correlation between submicroscopic chromosomal aberrations and VSDs.ResultsAmong the 151 VSD cases, 79 (52.3%) had isolated defects and 72 (47.7%) had additional ultrasound anomalies. Karyotype analysis identified 16 chromosomal abnormalities. Besides the 14 cases of chromosome abnormalities consistent with karyotype analysis, CMA identified an additional 20 cases (13.2%) of abnormal copy number variations (CNVs), of which 13 were pathogenetic CNVs, 5 were variations of uncertain clinical significance (VOUS) and 2 were benign CNVs. The detection rate of pathogenic CNVs in non-isolated-VSDs was significantly higher than that in isolated-VSDs (36.1% (26/72) vs. 1.3% (1/79), p = 0.001). We also found that CMA results indicating pathogenic abnormalities affected the rate of pregnancy termination.ConclusionsThis study showed that CMA combined with cytogenetic analysis is particularly effective in identifying CNVs in fetuses with VSDs and can have an effect on obstetrical outcomes. The elucidation of the etiology of VSDs suggested that gene mutations or other factors may be implicated.

Application of SNP-array technology in the genetic analysis of pediatric patients with growth retardation

To explore the value of single nucleotide polymorphism array (SNP-array) for the analysis of pediatric patients with growth retardation. One hundred eighty one children with growth retardation were enrolled. DNA was extracted from peripheral samples from the patients, and whole genome copy number variations (CNVs) were detected using Illumina Human Cyto SNP-12. All identified CNVs were further analyzed with reference to databases including ClinGen, ClinVar, DECIPHER, OMIM and DGV as well as comprehensive review of literature from PubMed to determine their pathogenicity. Forty seven patients (26%) with abnormal CNVs were detected, which included 12 known microdeletions/microduplications syndrome (26%), 10 pathogenic non-syndromic CNVs (21%), 3 numerical chromosome aberrations (6%), 3 unbalanced translocations (6%), 4 pathogenic mosaicisms (9%) and 15 cases with unknown clinical significance (32%). After excluding obvious numerical and/or structural chromosomal abnormalities, this study has detected 15 pathogenic microdeletions/microduplications sized 5 Mb or less, which may be missed by routine chromosomal karyotyping. In addition, there were 3 cases with loss of heterozygoisty (LOH) containing known or predicted imprinting genes as well as 2 cases with suspected parental consanguinity. SNP-array technology is a powerful tool for the genetic diagnosis of children with growth disorders with advantages of high resolution and improved accuracy.