Utility Of Chromosomal Microarray Analysis Research Articles

Prenatal chromosomal microarray analysis in a large Chinese cohort of fetuses with congenital heart defects: a single center study

Background and objectivesCongenital heart defect (CHD) is one of the most common birth defects. The aim of this cohort study was to evaluate the prevalence of chromosomal abnormalities and the clinical utility of chromosomal microarray analysis (CMA) in fetuses with different types of CHD, aiming to assist genetic counseling and clinical decision-making.MethodsIn this study, 642 fetuses with CHD were enrolled from a single center over a six-year period (2017–2022). Both conventional karyotyping and CMA were performed simultaneously on these fetuses.ResultsThe diagnostic yield of CMA in fetuses with CHD in our study was 15.3% (98/642). Our findings revealed a significant increase in the diagnostic yield of CMA compared to karyotyping in fetuses with CHD. Among CHD subgroups, the diagnostic yields were high in complex CHD (34.9%), conotruncal defects (28.6%), right ventricular outflow tract obstructive defects (RVOTO) (25.9%), atrioventricular septal defects (AVSD) (25.0%) and left ventricular outflow tract obstructive defects (LVOTO) (24.1%), while those in other CHD (10.6%) and septal defects (10.9%) were relatively low. The overall detection rate of clinically significant chromosomal abnormalities was significantly higher in the non-isolated CHD group compared to the isolated CHD group (33.1% vs. 9.9%, P < 0.0001). Interestingly, numerical chromosomal abnormalities were more likely to occur in the non-isolated CHD group than in the isolated CHD group (20.3% vs. 2.0%, P < 0.0001). The rate of termination of pregnancy (TOP)/Still birth in the non-isolated CHD group was significantly higher than that in the isolated CHD group (40.5% vs. 20.6%, P < 0.0001). Compared to the isolated CHD group, the detection rate of clinically significant chromosomal abnormalities was significantly higher in the group of CHD with soft markers (35.6% vs. 9.9%, P < 0.0001) and in the group of CHD with additional structural anomalies (36.1% vs. 9.9%, P < 0.0001).ConclusionsCMA is a reliable and high-resolution technique that should be recommended as the front-line test for prenatal diagnosis of fetuses with CHD. The prevalence of chromosomal abnormalities varies greatly among different subgroups of CHD, and special attention should be given to prenatal non-isolated cases of CHD, especially those accompanied by additional structural anomalies or soft markers.

Comparison of Chromosomal Microarray Analysis and Noninvasive Prenatal Testing in Pregnant Women with Fetal Ultrasonic Soft Markers.

This study aimed to assess the utility of chromosomal microarray analysis (CMA) and noninvasive prenatal testing (NIPT) in detecting clinically significant chromosomal abnormalities among fetuses presenting ultrasonic soft markers (USMs). A retrospective observational study, spanning from January 1, 2019, to September 30, 2022, enrolled 539 singleton pregnant women with fetal USMs at our center. Of these, 418 cases (77.6%) underwent NIPT, while 121 cases (22.4%) opted for invasive prenatal diagnosis post-appropriate genetic counseling. Cases with high-risk NIPT results proceeded to invasive prenatal diagnosis, where conventional karyotyping and CMA were concurrently performed. Further stratification was done based on the number of USMs, classifying cases into single-USM and multiple-USM groups. Of the 24 cases (4.5%) exhibiting abnormal findings, 17 presented numerical chromosomal abnormalities, 2 featured clinically significant copy number variations (CNVs), 3 showed variants of unknown significance (VOUS), 1 displayed LOH, and 1 exhibited chromosome nine inversion. Notably, 18 cases (75%) theoretically detectable by karyotyping (eg, sizes above 10Mb) and 16 cases (66.7%) detectable by NIPT for five common aneuploidies were identified. Six submicroscopic findings (25%) were exclusively detectable by CMA. The predominant clinically relevant aberrations were observed in the thickened nuchal-translucency (TNT) group (9/35, 25.7%), followed by the multiple soft markers group (3/32, 9.3%). In the NIPT group, the false positive rate was 1.22%, and the false negative rate was 0%. The prevalence of chromosome aneuploidy exceeded that of submicroscopic chromosomal imbalance in pregnant women with fetal USMs. NIPT demonstrated efficacy, particularly for soft markers like echogenic intracardiac focus. However, for those with TNT and multiple soft markers, invasive prenatal diagnosis, including CMA testing, is recommended as the primary investigative approach.

Clinical utility of chromosomal microarray analysis and whole exome sequencing in foetuses with oligohydramnios

Objectives To evaluate the clinical utility of chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in foetuses with oligohydramnios. Methods In this retrospective study, 126 fetuses with oligohydramnios at our centre from 2018 to 2021 were reviewed. The results of CMA and WES were analysed. Results One hundred and twenty-four cases underwent CMA and 32 cases underwent WES. The detection rate of pathogenic/likely pathogenic (P/LP) copy number variant (CNV) by CMA was 1.6% (2/124). WES revealed P/LP variants in 21.8% (7/32) of the foetuses. Six (85.7%, 6/7) foetuses showed an autosomal recessive inheritance pattern. Three (42.9%, 3/7) variants were involved in the renin–angiotensin–aldosterone system (RAAS), which are the known genetic causes of autosomal recessive renal tubular dysgenesis (ARRTD). Conclusion CMA has low diagnostic utility for oligohydramnios, while WES offers obvious advantages in improving the detection rate. WES should be recommended for fetuses with oligohydramnios.

Should prenatal chromosomal microarray analysis be offered for isolated ventricular septal defect? A single-center retrospective study from China.

ObjectiveTo evaluate the utility of chromosomal microarray analysis (CMA) in fetuses with isolated ventricular septal defect (VSD) and to explore the favorable factors for predicting spontaneous closure of defects.MethodsThe study included 436 singleton pregnancies seen at a referral prenatal diagnosis center, between January 2016 and May 2020, of which 168 fetuses with isolated VSD were diagnosed in the prenatal setting. VSD was classified as an isolated VSD whether it had ultrasound soft markers or not. All patients underwent testing employing quantitative fluorescent polymerase chain reaction (QF-PCR) and CMA as the first-line genetic detection strategies, mainly in amniotic fluid and umbilical blood samples. Rates of chromosomal abnormalities were compared by subgroups of isolated VSD (muscular or perimembranous). Binary logistic regression analysis was performed to predict the independent determinants of spontaneous closure by 2 years.ResultsOverall, the CMA identified clinically significant copy number variations (CNVs) in 7/168 (4.2%) fetuses and variants of unknown significance (VOUS) in 15/168 (8.9%). Muscular and perimembranous VSDs were found in 53.6 and 46.4%, respectively. Clinically significant relevant subchromosomal aberrations were revealed in seven (9.0%) perimembranous VSDs compared with none in 90 muscular defects (P < 0.01). The median initial size of the defect in the muscular VSDs was 2.2(1.8–2.7) mm, as compared to that of 2.8 (2.2–3.2) mm in the perimembranous VSDs group (p = 0.000). In muscular vs. perimembranous VSDs, spontaneous closure occurred more frequently and earlier [40.0 vs. 15.4% in utero (p = 0.000), 61.1 vs. 30.8% at 1-year (p = 0.000), and 75.6 vs. 42.3% at 2-year (P = 0.000)]. Postnatal surgical closure was warranted in 4/90 (4.4%) of the infants with muscular VSDs, as compared to 29/71 (40.8%) with perimembranous defects (p = 0.000). Furthermore, isolated muscular type VSD, smaller defect size, and maternal age of less than 35 years are all positive predictors of spontaneous closure of the defects.ConclusionThis study highlighted the value of microarray for unbalanced subchromosomal abnormalities in fetuses with isolated VSD, particularly in the perimembranous defects. The detection of an isolated muscular VSD prenatally may be considered a benign or likely benign finding; in contrast, for perimembranous VSD, a prenatal CMA should be offered.

Utility of chromosomal microarray analysis for the exploration of isolated and severe fetal growth restriction diagnosed before 24weeks' gestation.

This study aimed to evaluate the utility of chromosomal microarray analysis (CMA), for the genetic exploration of isolated and severe intrauterine growth restriction (IUGR) diagnosed before 24weeks gestation (WG). This retrospective study included singleton fetuses diagnosed with severe IUGR without structural anomalies before 24 WG referred between 2013 and 2021 who underwent prenatal genetic analysis. IUGR was defined by estimated fetal weight ≤3rd centile for gestational age. Genetic analysis, including QF-PCR and CMA, was systematically offered as part of the etiologic evaluation. Of 101 referred fetuses, CMA and QF-PCR were performed in 67 fetuses. Among these 67 cases, a total of 10.5% (7/67) chromosomal abnormalities were detected. CMA detected three pathogenic copy number variants (CNV) (3/67, 4.5%) and three variants of unknown signification (VUS) (3/67, 4.5%). Karyotype detected one chromosomal abnormality. All of the QF-PCR were normal. Two fetuses with pathogenic CNV shows Doppler abnormalities. Our study found that in fetuses with severe, isolated, and very early-onset growth restriction, the rate of pathogenic CNV detected by CMA was 4.5%. Although this cohort is too small to draw a definitive conclusion, the presence of Doppler abnormalities couldn't exclude the possibility of genetic abnormalities.

Detection of copy number variants and genes by chromosomal microarray in an Emirati neurodevelopmental disorders cohort.

Copy number variations (CNVs) are highly implicated in the etiology of neurodevelopmental disorders (NDDs), and chromosomal microarray analysis (CMA) has been recommended as a first-tier test for many NDDs. We undertook a study to identify clinically relevant CNVs and genes in an ethnically homogenous population of the United Arab Emirates. We genotyped 98 patients with NDDs using genome-wide chromosomal microarray analysis, and observed 47.1% deletion and 52.9% duplication CNVs, of which 11.8% are pathogenic, 23.5% are likely pathogenic, and 64.7% VOUS. The average size of copy number losses (3.9Mb) was generally higher than of gains (738.4kb). Analysis of VOUS CNVs for constrained genes (enrichment for brain critical exons and high pLI genes) yielded 7 unique genes. Among these 7 constrained genes, we propose FNTA and PXK as potential candidate genes for neurodevelopmental disorders, which warrants further investigation. Thirty-two overlapping CNVs (Decipher and ClinVar) containing the FNTA gene were previously identified in NDD patients and 6 overlapping CNVs (Decipher and ClinVar) containing the PXK gene were previously identified in NDD patients. Our study supports the utility of CMA for CNV profiling which aids in precise genetic diagnosis and its integration into therapeutics and management of NDD patients.

Clinical utility of chromosomal microarray analysis to detect copy number variants: Experience in a single tertiary hospital

Clinical utility of chromosomal microarray analysis to detect copy number variants: Experience in a single tertiary hospital

Should prenatal chromosomal microarray analysis be offered for isolated fetal growth restriction? A French multicenter study

Compared with standard karyotype, chromosomal microarray analysis improves the detection of genetic anomalies and is thus recommended in many prenatal indications. However, evidence is still lacking on the clinical utility of chromosomal microarray analysis in cases of isolated fetal growth restriction. This study aimed to estimate the proportion of copy number variants detected by chromosomal microarray analysis and the incremental yield of chromosomal microarray analysis compared with karyotype in the detection of genetic abnormalities in fetuses with isolated fetal growth restriction. This retrospective study included all singleton fetuses diagnosed with fetal growth restriction and no structural ultrasound anomalies and referred to 13 French fetal medicine centers over 1 year in 2016. Fetal growth restriction was defined as an estimated fetal weight of <tenth percentile for gestational age identified in ultrasound reports. For this analysis, we selected fetuses who underwent invasive genetic testing with karyotype and chromosomal microarray analysis results. Data were obtained from medical records and ultrasound databases and postmortem and placental examination reports in case of spontaneous stillbirths and terminations of pregnancy. Following the American College of Medical Genetics and Genomics guidelines, copy number variants were classified into 5 groups as following: pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign. Of 682 referred fetuses diagnosed with isolated fetal growth restriction, both karyotype and chromosomal microarray analysis were performed in 146 fetuses. Overall, the detection rate of genetic anomalies found by chromosomal microarray analysis was estimated to be 7.5% (11 of 146 [95% confidence interval, 3.3-11.8]), including 10 copy number variants classified as pathogenic and 1 copy number variant classified as likely pathogenic. Among the 139 fetuses with normal karyotype, 5 were detected with pathogenic and likely pathogenic copy number variants, resulting in an incremental yield of 3.6% (95% confidence interval, 0.5-6.6) in chromosomal microarray analysis compared with karyotype. All fetuses detected with pathogenic or likely pathogenic copy number variants resulted in terminations of pregnancy. In addition, 3 fetuses with normal karyotype were detected with a variant of unknown significance (2.1%). Among the 7 fetuses with abnormal karyotype, chromosomal microarray analysis did not detect trisomy 18 mosaicism in all fetuses. Our study found that compared with karyotype, chromosomal microarray analysis improves the detection of genetic anomalies in fetuses diagnosed with isolated fetal growth restriction. These results support the use of chromosomal microarray analysis in addition to karyotype for isolated fetal growth restriction.

Pediatrik Nörolojide Klinik Fenotipler ve Kromozomal Mikrodelesyon/Duplikasyonlar Arasındaki İlişki

Aim: The aim of this study was to determine the diagnostic utility of chromosomal microarray analysis (CMA) in daily pediatric neurology practice and to identify the guiding clinical parameters for patients requiring this test. Material and Methods: The CMA results for 91 patients with global developmental delay/intellectual disability (GDD/ID) admitted to our pediatric neurology clinic for various reasons between 2018 and 2020 were examined. Demographical and clinical data for 34 patients (37.4%) in whom del/dup was determined at CMA and 57 patients (62.6%) with normal CMA were compared. Results: There was no statistically significant difference between two groups in terms of demographic characteristics such as age, gender, type of delivery, gestational age, etc. Dysmorphisms, hypotonia, myelination abnormalities were significantly more frequent in patients with del/dup than in patients with normal result. The frequency of macrocephaly and obesity was higher in the normal group, and that of generalized seizures was higher among epileptic patients in this group. Nineteen (55.9%) of the 34 cases who have del/dup detected at analysis were regarded as pathogenic, 15 (44.1%) as uncertain clinical significance (likely pathogenic, likely benign and no subclassification). Conclusion: Since CMA is an expensive, laborious, and time-consuming test, considering clinical parameters when requesting CMA will yield high diagnostic efficiency. A high possibility of copy number variants may be predicted in GDD/ID patients with dysmorphisms, hypotonia, and myelination delay. CMA should represent the genetic analysis of choice in pediatric neurology practice in case of no finding suggesting a different etiology in these patients.

Clinical utilization of chromosomal microarray analysis for the genetic analysis in subgroups of pregnancy loss

Objective The underlying etiologies of pregnancy loss are heterogeneous and in many cases unexplained. This study was to explore the genetic causes of early and late pregnancy loss using chromosomal microarray analysis (CMA). Methods A cohort of 222 specimens of conceptions underwent genetic analysis using Affymetrix CytoScan 750 K arrays, which includes both SNP markers and copy number markers. Results Of the 222-products of conception (POC), the overall detection rate for clinical significantly chromosomal anomalies was 40.54%, including 53 autosomal aneuploidy (23.87%), 16 sex chromosome aneuploidy (7.21%), 5 mutiple aneuploidy (2.25%), 4 triploidy (1.80%), and 12 pathogenic copy number variants (pCNVs) (5.41%). In addition, variants of uncertain significance and loss of heterozygosity were detected in 9 samples and 2 samples, respectively. The detection rates for total chromosomal abnormalities, autosomal aneuploidy, sex chromosome aneuploidy, multiple aneuploidy, and triploidy in specimens of early pregnancy loss was higher than that of late pregnancy loss, while had lower detection rate of pCNVs. Moreover, the detection rate in POC of mothers younger than 35 years was lower than that of advanced maternal age. The detection rate was 40.57% in POC of mothers with adverse pregnancy histories, in which was comparable with that of mothers without adverse pregnancy histories. Conclusions CMA yielded a superior detection rate in early pregnancy loss than that of late pregnancy loss. Moreover, the incidence of chromosome abnormality in cases with advanced maternal age was higher than that of cases with younger maternal age, while adverse pregnancy history seemed not to be the factors affecting the detection rate for chromosomal abnormality in pregnancy loss.

Genetic testing in fetuses with isolated agenesis of the corpus callosum

Purpose The objectives of this study were to explore genetics pathogenesis of isolated agenesis of corpus callosum (ACC) and assess the utility of chromosomal microarray analysis (CMA) for genetic diagnosis of isolated ACC. Methods We analyzed the genomes of 16 fetuses with isolated ACC using Afymetrix CytoScan HD arrays and conducted further bioinformatic analysis for one proband fetus with an abnormal copy number variation (CNV). Results Of the 16 fetal samples examined, two (12.5%) had pathogenic CNVs and three (18.75%) had variants of unknown significance. Two cases, case 2 and case 9, were found to have pathogenic CNVs. Bioinformatic analyses indicated that the CNV of one fetus (case 9) contained 115 annotated coding genes, five of which (SLC6A5, BDNF, ELP4, PAX6, and SLC1A2) have been associated with neurodevelopment. Three of these genes (SLC1A2, BDNF, and PAX6) may play a key role in ACC development. GO cluster analysis of the implicated genes revealed strong representations of protein binding and metal ion binding functions. KEGG pathway analysis pointed to four pathways: longevity regulating pathway, amyotrophic lateral sclerosis, cocaine addiction, and autophagy-animal. Conclusions BDNF, SLC1A2, and PAX6 may be involved in the development of isolated ACC. CMA is a feasible technology for prenatal diagnosis of isolated ACC.

A feasible diagnostic approach for the translocation carrier from the indication of products of conception

BackgroundChromosome translocations are rare but frequently associated with infertility. The objective of this study is to investigate the feasibility of using chromosomal microarray analysis (CMA) on products of conception (POC) samples as an indicator of parental balanced translocation. From January 2011 to December 2016, CMA using Affymetrix Cytoscan™750K array was performed on 1294 POC samples in our hospital. Karyotyping and fluorescence in situ hybridization (FISH) using parental blood samples were performed to validate the origin of subchromosomal copy number variations (CNVs).ResultsIn the 1294 cases of POCs, we detected CNVs of terminal duplication and deletion that imply unbalanced translocation derivatives in 16 cases, and accurate diagnosis with the parental study was made in all the cases by karyotyping and/or FISH. In 10/16 (62.5%) of these cases, CNVs were inherited from one carrier parent of balanced translocation (Cases 1 to 10), while 6/16 (37.5%) cases occurred de novo (Cases 11 to 16).ConclusionThis study clearly illustrated the importance of the utilization of CMA on POC, followed by parental karyotyping and FISH to better characterize CNVs. This approach is especially useful for couples in whom one partner carries a cryptic/submicroscopic balanced translocation but has an apparently normal karyotype.

"Set in Stone" or "Ray of Hope": Parents' Beliefs About Cause and Prognosis After Genomic Testing of Children Diagnosed with ASD.

Despite increasing utilization of chromosomal microarray analysis (CMA) for autism spectrum disorders (ASD), limited information exists about how results influence parents' beliefs about etiology and prognosis. We conducted in-depth interviews and surveys with 57 parents of children with ASD who received CMA results categorized as pathogenic, negative or variant of uncertain significance. Parents tended to incorporate their child's CMA results within their existing beliefs about the etiology of ASD, regardless of CMA result. However, parents' expectations for the future tended to differ depending on results; those who received genetic confirmation for their children's ASD expressed a sense of concreteness, acceptance and permanence of the condition. Some parents expressed hope for future biomedical treatments as a result of genetic research.

Contribution of genomic copy-number variations in prenatal oral clefts: a multicenter cohort study.

We sought to investigate the utility of chromosomal microarray analysis (CMA) for prenatal diagnosis of oral clefts, as compared with traditional chromosome analysis, for improved prenatal genetic counseling and discovery of a potential correlation between genotype and oral cleft. This retrospective analysis encompassed 270 prenatal oral cleft cases with documented detailed ultrasound findings and CMA results from four referral centers. Detection rates for pathogenic copy-number variants (CNVs) were calculated and compared with cases for which chromosome analysis was also performed. The overall detection rate was 14.8% (40/270) for pathogenic CNVs by CMA, 7.2% (9/125) for the nonsyndromic cases, and 21.4% (31/145) for the syndromic cases. Of the nonsyndromic cases with ultrasound soft markers, 20% (5/25) were identified with pathogenic CNVs. CMA showed an improved detection rate of 15.3% (29/190) compared with 10.5% (20/190) for chromosome analysis. This study not only highlights the improved detection of chromosomal defects by CMA in prenatal oral clefts but also deepens our understanding of oral clefts. The results suggest that CMA is highly recommended in prenatal invasive genetic testing not only for syndromic oral cleft cases but also for nonsyndromic cases with soft markers. Candidate genes including CRKL, AKAP8, SYDE1, BRD4 are worthy of further investigation regarding their role in human palatogenesis.Genet Med 18 10, 1052-1055.

Cytogenomic Delineation and Clinical Characterization of Three Cases of MECP2 Duplication Syndrome

The methyl-CpG-binding protein 2 gene (MECP2) on the X chromosome encodes an essential epigenetic regulator in human postnatal brain development. Increased dosage of MECP2 causes a severe syndromic form of intellectual disability, the MECP2 duplication syndrome. Males with this syndrome have a progressive neurological disorder, severe to profound intellectual disability, epilepsy and recurrent respiratory infections. We report three cases with copy number gain in Xq28 involving the MECP2 gene. The gains were detected by chromosomal microarray analysis and ranged in size from 300 kb to 4.96 Mb. The three boys were aged between 3 and 16 years old. All three had development delay and no speech. In addition, one patient was diagnosed with Lennox-Gastaut syndrome and another had a Dandy Walker variant. Their clinical features were compared with other reported cases. We concluded that all three patients’ clinical features were due to the Xq28 duplication, which confirmed the utility of chromosomal microarray analysis as a first-tier test in patients with unexplained intellectual disability. With a specific genetic diagnosis, we were able to provide appropriate anticipatory guidance for these patients and their families.

Clinical Utility of DNA Arrays in Detecting Chromosomal Aberrations Associated with High-Risk Philadelphia-Like Acute Lymphoblastic Leukemia

The Philadelphia (Ph)-like Acute Lymphoblastic Leukemia (ALL) is a recently described class of B-cell ALL, characterized by an expression pattern similar to the one observed in the t(9;22) positive subtype. ‘Ph-like’ leukemias are frequently resistant to standard chemotherapy and have a high probability of relapse; however, they were shown to respond to treatment with tyrosine kinase inhibitors (TKIs), since they are characterized by activated kinase signature. This study evaluated the utility of chromosomal microarray analysis (CMA) in detecting genetic abnormalities associated with Ph-like ALL.

Clinical utility of chromosomal microarray analysis in prenatal diagnosis: report of first 6 months in clinical practice

Objective: We studied the clinical utility of chromosomal microarray analysis (CMA) in prenatal diagnosis in a clinical setting in New York City.Methods: Our center began offering CMA to pregnant women undergoing invasive diagnostic procedures for an abnormal structural finding on ultrasound, maternal age of 35 years or older, or elevated risk on aneuploidy screening, beginning March 2012. Our first six months experience is reported.Results: Benign familial variants were the most common finding (16/22 fetuses). Variants of uncertain significance were frequent, especially when fathers were not available for testing (4/22 fetuses). Most patients undertook CMA as part of evaluation of an ultrasound anomaly (52%). One patient terminated a pregnancy based on an ultrasound finding in the setting of a benign familial variant on CMA, and a second terminated a pregnancy based on a copy number variant identified on CMA.Conclusion: For CMA to be maximally useful in prenatal diagnosis, parental DNA samples as well as robust datasets to provide predictive phenotypic information are required. The most common reason for undertaking CMA was to evaluate an ultrasound anomaly, and benign familial variants were a common finding. Genetic services are required to provide pre- and post-test genetic counseling and help families interpret results.

Cleft Lip and Palate in a Patient with 5q35.2-q35.3 Microdeletion: The Importance of Chromosomal Microarray Testing in the Craniofacial Clinic

We report on a 3½-year-old African American female with a 1.63 Mb microdeletion in 5q35.2-q35.3. This deletion includes NSD1, the gene that causes Sotos syndrome. The patient has unilateral cleft lip and palate (CLP) status postrepair, an unrepaired alveolar cleft, speech delay, global developmental delay, macrocephaly, mild cerebral palsy, and a patent ductus arteriosus status postrepair. Dysmorphic features include a prominent forehead and midface hypoplasia. This is one of the first cases of CLP associated with Sotos syndrome and emphasizes the utility of chromosomal microarray analysis in patients with more than isolated CLP in the Craniofacial Clinic.

Chromosomal microarray analysis as a first-line test in pregnancies with a priori low risk for the detection of submicroscopic chromosomal abnormalities

In this study, we aimed to explore the utility of chromosomal microarray analysis (CMA) in groups of pregnancies with a priori low risk for detection of submicroscopic chromosome abnormalities, usually not considered an indication for testing, in order to assess whether CMA improves the detection rate of prenatal chromosomal aberrations. A total of 3000 prenatal samples were processed in parallel using both whole-genome CMA and conventional karyotyping. The indications for prenatal testing included: advanced maternal age, maternal serum screening test abnormality, abnormal ultrasound findings, known abnormal fetal karyotype, parental anxiety, family history of a genetic condition and cell culture failure. The use of CMA resulted in an increased detection rate regardless of the indication for analysis. This was evident in high risk groups (abnormal ultrasound findings and abnormal fetal karyotype), in which the percentage of detection was 5.8% (7/120), and also in low risk groups, such as advanced maternal age (6/1118, 0.5%), and parental anxiety (11/1674, 0.7%). A total of 24 (0.8%) fetal conditions would have remained undiagnosed if only a standard karyotype had been performed. Importantly, 17 (0.6%) of such findings would have otherwise been overlooked if CMA was offered only to high risk pregnancies.The results of this study suggest that more widespread CMA testing of fetuses would result in a higher detection of clinically relevant chromosome abnormalities, even in low risk pregnancies. Our findings provide substantial evidence for the introduction of CMA as a first-line diagnostic test for all pregnant women undergoing invasive prenatal testing, regardless of risk factors.

Clinical utility of chromosomal microarray analysis in invasive prenatal diagnosis

Novel methodologies for detection of chromosomal abnormalities have been made available in the recent years but their clinical utility in prenatal settings is still unknown. We have conducted a comparative study of currently available methodologies for detection of chromosomal abnormalities after invasive prenatal sampling. A multicentric collection of a 1-year series of fetal samples with indication for prenatal invasive sampling was simultaneously evaluated using three screening methodologies: (1) karyotype and quantitative fluorescent polymerase chain reaction (QF-PCR), (2) two panels of multiplex ligation-dependent probe amplification (MLPA), and (3) chromosomal microarray-based analysis (CMA) with a targeted BAC microarray. A total of 900 pregnant women provided informed consent to participate (94% acceptance rate). Technical performance was excellent for karyotype, QF-PCR, and CMA (~1% failure rate), but relatively poor for MLPA (10% failure). Mean turn-around time (TAT) was 7 days for CMA or MLPA, 25 for karyotype, and two for QF-PCR, with similar combined costs for the different approaches. A total of 57 clinically significant chromosomal aberrations were found (6.3%), with CMA yielding the highest detection rate (32% above other methods). The identification of variants of uncertain clinical significance by CMA (17, 1.9%) tripled that of karyotype and MLPA, but most alterations could be classified as likely benign after proving they all were inherited. High acceptability, significantly higher detection rate and lower TAT, could justify the higher cost of CMA and favor targeted CMA as the best method for detection of chromosomal abnormalities in at-risk pregnancies after invasive prenatal sampling.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-011-1095-5) contains supplementary material, which is available to authorized users.