Karyotype versus genomic hybridization for the prenatal diagnosis of chromosomal abnormalities: a metaanalysis

doi:10.1016/j.ajog.2014.10.011

American Journal of Obstetrics and Gynecology

Volume 212, Issue 3, March 2015, Pages 330.e1-330.e10

Presented at the 29th Annual Scientific Meeting of the Colombian Obstetrical and Gynecologic Society, Medellin, Colombia, May 28-31, 2014.

https://doi.org/10.1016/j.ajog.2014.10.011 Get rights and content

Objective

The aim of this study was to determine the diagnostic accuracy of comparative genomic hybridization (CGH) compared with karyotyping for the detection of numerical and structural chromosomal alterations in prenatal diagnosis.

Study Design

A metaanalysis was performed using searches of PubMed, EMBASE, CENTRAL, Cochrane Register of Diagnostic Test Accuracy Studies, Google Scholar, gray literature, and reference manuals. No language restriction was imposed. We included cross-sectional, cohort, and case-control studies published from January 1980 through March 2014 in the analysis. Studies of pregnant women who received chorionic villus biopsies, amniocentesis, or cordocentesis and then underwent CGH and karyotype analysis were included. Two independent reviewers assessed each study by title, abstract, and full text before its inclusion in the analysis. Methodological quality was assessed using QUADAS2, and a third reviewer resolved any disagreement. Conclusions were obtained through tests (sensitivity, specificity, and likelihood ratios) for the presence of numerical and structural chromosomal abnormalities. The reference used for these calculations was the presence of any abnormalities in either of the 2 tests (karyotype or CGH), although it should be noted that in most cases, the karyotyping test had a lower yield compared with CGH. Statistical analysis was performed in RevMan 5.2 and the OpenMeta[Analyst] program.

Results

In all, 137 articles were found, and 6 were selected for inclusion in the systematic review. Five were included in the metaanalysis. According to the QUADAS2 analysis of methodology quality, there is an unclear risk for selection bias and reference and standard tests. In the other elements (flow, time, and applicability conditions), a low risk of bias was found. CGH findings were as follows: sensitivity 0.939 (95% confidence interval [CI], 0.838–0.979), I² = 82%; specificity 0.999 (95% CI, 0.998–1.000), I² = 0%; negative likelihood ratio 0.050 (95% CI, 0.015–0.173), I² = 0%; and positive likelihood ratio 1346.123 (95% CI, 389–4649), I² = 0%. Karyotype findings were as follows: sensitivity 0.626 (95% CI, 0.408–0.802), I² = 93%; specificity 0.999 (95% CI, 0.998–1.000), I² = 0%; negative likelihood ratio 0.351 (95% CI, 0.101–1.220), I² = 0%; and positive likelihood ratio 841 (95% CI, 226–3128), I² = 10%.

Conclusion

This systematic review provides evidence of the relative advantage of using CGH in the prenatal diagnosis of chromosomal and structural abnormalities over karyotyping, demonstrating significantly higher sensitivity with similar specificity.

Section snippets

Materials and Methods

This study was conducted according to the recommendations of the Cochrane Collaboration and is reported following the PRISMA Statement. The protocol was registered in the international prospective register of systematic reviews (PROSPERO): CRD42014007627.

We designed a search strategy for studies published in MEDLINE via PubMed, CENTRAL, Cochrane Register of Diagnostic Test Accuracy Studies, and EMBASE. The search strategy was specific for each database and included a combination of the medical

Study selection

In all, 137 articles were found with the described search strategies; after exclusions, 6 and 5 studies were included in qualitative (general description of the data) and metaanalysis, respectively (Armengol et al⁷ [2012], Fiorentino et al¹⁴ [2011], Maya et al¹⁵ [2010], Wapner et al¹⁶ [2012], and Van den Veyver et al¹⁷ [2009]) (Figure 1).

Characteristics of included studies

In all, 9974 pregnant patients were identified in the studies, with a median of 971 (interquartile range, 269–4282) patients per study. With respect to the

Summary of major findings

In summary, 6 studies were included in the qualitative analysis,7, 11, 14, 15, 16, 17 and one of these studies was excluded from the quantitative analysis because it did not contain the requisite data.¹¹ A total of 9974 pregnant women were included in the studies. The sensitivity and specificity were 94.5% and 98.7%, respectively, for CGH compared with the gold standard. The sensitivity and specificity values for karyotype alone were 67.3% and 99%, respectively.

Generation of the gold standard

CGH is used in prenatal diagnosis

References (29)

M. Querejeta et al.
Diagnóstico prenatal y array-CGH II: gestaciones de bajo riesgo
Diagnostico Prenat
(2012)
D.T. Miller et al.
Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies
Am J Hum Genet
(2010)
D.A. Regier et al.
Value for money? Array genomic hybridization for diagnostic testing for genetic causes of intellectual disability
Am J Hum Genet
(2010)
M. Mori et al.
Prenatal diagnosis and comparative genomic hybridization (CGH)-array (I); high-risk pregnancies
Diagn Prenat
(2012)
C. Schluth-Bolard et al.
Cryptic genomic imbalances in de novo and inherited apparently balanced chromosomal rearrangements: array CGH study of 47 unrelated cases
Eur J Med Genet
(2009)
F. Mujezinovic et al.
Technique modifications for reducing the risks from amniocentesis or chorionic villus sampling
Cochrane Database Syst Rev
(2012)
F. Alvarez-Nava et al.
Prenatal maternal blood screening for the detection of fetal chromosomal abnormalities: clinical importance of the rate of false positives
Invest Clin
(2003)
J. Friedman et al.
Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization
BMC Genomics
(2009)
L. Armengol et al.
Clinical utility of chromosomal microarray analysis in invasive prenatal diagnosis
Hum Genet
(2012)
A. Breman et al.
Prenatal chromosomal microarray analysis in a diagnostic laboratory; experience with >1000 cases and review of the literature
Prenat Diagn
(2012)

L.G. Shaffer et al.

Experience with microarray-based comparative genomic hybridization for prenatal diagnosis in over 5000 pregnancies

Prenat Diagn

(2012)

C.-N. Lee et al.

Clinical utility of array comparative genomic hybridization for prenatal diagnosis: a cohort study of 3171 pregnancies; editorial comment

BJOG

(2012)

S.C. Hillman et al.

Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis

Ultrasound Obstet Gynecol

(2011)

Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The Cochrane...

Cited by (34)

Single nucleotide polymorphism array versus karyotype for prenatal diagnosis in fetuses with abnormal ultrasound: A systematic review and meta-analysis
2022, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
It is noteworthy to mention that most of these recommendations were based on studies which had compared aCGH with conventional karyotype [16–18]. While the accumulated data from studies evaluating aCGH versus conventional karyotype have been systematically appraised [20,21], there is paucity of such reviews in investigating the role of SNP array as a prenatal diagnostic tool. We decided to estimate the incremental yield of SNP array over conventional karyotype in detecting chromosomal abnormalities for prenatal diagnosis in fetuses with an abnormal ultrasound.
To estimate the incremental yield of single nucleotide polymorphism (SNP) array over karyotype and to assess the diagnostic accuracy of SNP array as a stand-alone test versus SNP array with karyotype in detecting chromosomal abnormalities for prenatal diagnosis in women with an abnormal fetal ultrasound.
Studies in which SNP array and karyotype had been used for diagnosing chromosomal aberrations in fetuses with abnormal ultrasound findings were included. A systematic search of relevant studies published in the English language in EMBASE, PubMed, CENTRAL, CDSR (Cochrane database of systematic reviews), SCOPUS and Web of science between 1996 and May 2020 was performed. Primary outcome was incremental yield of SNP array over karyotype (number of patients with abnormalities detected by SNP array over number of patients with normal karyotype). Other outcomes included diagnostic accuracy of SNP array alone versus SNP array and karyotype for prenatal diagnosis. Pooled sensitivities, specificities, and their 95% confidence intervals (CI) were presented.
Seven studies were included. The incremental yield of SNP array over karyotype was 8% (95% Confidence interval, CI 4–12%) while incremental yield of karyotype over SNP array in foetus with abnormal ultrasound was 0% (95% CI 0–1%). The agreement between SNP array and karyotype was 92%. The variant of unknown significance rates ranged between 4 and 8 %. The pooled sensitivity and specificity of SNP array versus SNP array and karyotype was 0.97 (95% CI 0.92–0.99) and 1.00 (95% CI1.00–1.00), respectively.
SNP array provides additional information on chromosomal abnormalities over and above conventional karyotype. When used as a stand-alone test, SNP array performs favourably as a diagnostic modality when compared against SNP array and karyotype for prenatal diagnosis with an abnormal fetal ultrasound.
Should prenatal chromosomal microarray analysis be offered for isolated fetal growth restriction? A French multicenter study
2021, American Journal of Obstetrics and Gynecology
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.
Hirschsprung disease with Edward syndrome: A rare association: A case report
2021, International Journal of Surgery Case Reports
Citation Excerpt :
However, the mother did not have her antenatal scans done and thus the prenatal diagnosis was missed. Though G-band karyotyping of peripheral blood after birth can help to make the diagnosis of ES [11]. In our case, the clinical features in our case were obvious to support the diagnosis, and thus no karyotyping was performed.
Edward's syndrome (ES) occurs as a result of trisomy of chromosome 18 and is associated with multisystem congenital anomalies. The association of ES with various gastrointestinal malformations but Hirschsprung disease (HD) is well documented.
A female infant on her 5th day of life presented with episodes of bilious vomiting along with abdominal distension and no passage of stool. The child had a small head and prominent occiput, low set abnormal ears, small jaw, upturned nose, widely spaced eyes, small neck with widely spaced nipples, clenched hands with overlapping fingers, flexed big toe, and prominent heels.
Edward syndrome is associated with multisystem congenital abnormalities of which gastrointestinal abnormalities make up the most part. The condition can be identified by fetal ultrasound screening. Surgical correction of associated congenital anomalies at different times along with lifelong supportive management is important.
Edward syndrome can present as Hirschsprung disease as a part of associated gastrointestinal Malformation. Often, early identification and termination of the pregnancy in antenatal life can reduce the suffering. Surgical correction of associated anomalies along with supportive care forms the cornerstone of management. However, the prognosis remains poor.
Genetic testing
2019, Applied Genomics and Public Health
In modern medicine, new concepts and technologies, such as personalized medicine, have been introduced, improving the prevention and/or therapeutic approach of an individual. Undoubtedly, personalized medicine interventions have become a valuable tool for public health, and for this reason the majority of the scientific community as a whole and pharmaceutical companies are focusing on the continuous development of new genetic tests and the improvement of existing technologies. In recent years, molecular genetic testing is gradually being integrated into everyday clinical practice offering a wide range of benefits and services. Despite their widespread use, end users still have a poor knowledge of their use, as well as about their potentials and limitations, and also regarding the results’ interpretation. Moreover, the use of genetic tests is not possible in some cases due to the high costs and on the other hand due to the failure of insurance companies to provide an allowance. This chapter provides an overview of the main types of genetic tests, their advantages and limitations, and their usefulness in personalized medicine and in clinical practice and disease diagnosis.
Prospective chromosome analysis of 3429 amniocentesis samples in China using copy number variation sequencing
2018, American Journal of Obstetrics and Gynecology
Next-generation sequencing is emerging as a viable alternative to chromosome microarray analysis for the diagnosis of chromosome disease syndromes. One next-generation sequencing methodology, copy number variation sequencing, has been shown to deliver high reliability, accuracy, and reproducibility for detection of fetal copy number variations in prenatal samples. However, its clinical utility as a first-tier diagnostic method has yet to be demonstrated in a large cohort of pregnant women referred for fetal chromosome testing.
We sought to evaluate copy number variation sequencing as a first-tier diagnostic method for detection of fetal chromosome anomalies in a general population of pregnant women with high-risk prenatal indications.
This was a prospective analysis of 3429 pregnant women referred for amniocentesis and fetal chromosome testing for different risk indications, including advanced maternal age, high-risk maternal serum screening, and positivity for an ultrasound soft marker. Amniocentesis was performed by standard procedures. Amniocyte DNA was analyzed by copy number variation sequencing with a chromosome resolution of 0.1 Mb. Fetal chromosome anomalies including whole chromosome aneuploidy and segmental imbalances were independently confirmed by gold standard cytogenetic and molecular methods and their pathogenicity determined following guidelines of the American College of Medical Genetics for sequence variants.
Clear interpretable copy number variation sequencing results were obtained for all 3429 amniocentesis samples. Copy number variation sequencing identified 3293 samples (96%) with a normal molecular karyotype and 136 samples (4%) with an altered molecular karyotype. A total of 146 fetal chromosome anomalies were detected, comprising 46 whole chromosome aneuploidies (pathogenic), 29 submicroscopic microdeletions/microduplications with known or suspected associations with chromosome disease syndromes (pathogenic), 22 other microdeletions/microduplications (likely pathogenic), and 49 variants of uncertain significance. Overall, the cumulative frequency of pathogenic/likely pathogenic and variants of uncertain significance chromosome anomalies in the patient cohort was 2.83% and 1.43%, respectively. In the 3 high-risk advanced maternal age, high-risk maternal serum screening, and ultrasound soft marker groups, the most common whole chromosome aneuploidy detected was trisomy 21, followed by sex chromosome aneuploidies, trisomy 18, and trisomy 13. Across all clinical indications, there was a similar incidence of submicroscopic copy number variations, with approximately equal proportions of pathogenic/likely pathogenic and variants of uncertain significance copy number variations. If karyotyping had been used as an alternate cytogenetics detection method, copy number variation sequencing would have returned a 1% higher yield of pathogenic or likely pathogenic copy number variations.
In a large prospective clinical study, copy number variation sequencing delivered high reliability and accuracy for identifying clinically significant fetal anomalies in prenatal samples. Based on key performance criteria, copy number variation sequencing appears to be a well-suited methodology for first-tier diagnosis of pregnant women in the general population at risk of having a suspected fetal chromosome abnormality.
Genetics of recurrent miscarriage and fetal loss
2017, Best Practice and Research: Clinical Obstetrics and Gynaecology
Citation Excerpt :
These techniques can be subdivided in to whole genome techniques (CGH, array-CGH) and chromosome-specific techniques (FISH, qPCR, QF-PCR). A recent systematic review by Saldarriaga et al. [59] concluded that CGH exhibits higher sensitivity with similar specificity what does karyotyping, and clinical heterogeneity has to be considered, thereby, confirming the data from previous meta-analyses and reviews [4]. Although the value of knowledge on the prevalence of cytogenetic abnormalities in miscarriage samples is undisputed, current data differ as to the usefulness of molecular techniques and karyotyping of miscarriage samples in routine clinical practice.
Despite years of research, miscarriage, particularly when recurrent, continues to pose a medical challenge. An embryo chromosomal error is responsible for 50–60% of recurrent cases; however, up to 30–50% remains an enigma. Successful pregnancy involves different maternal physiologic changes and certain complex interactions between the fetus and the mother by cytokines, angiogenic mediators and hormones. To date, research lines have focused on genetic and epigenetic polymorphisms related mainly to immune response and inflammatory mediators, and have yielded a significant relationship between recurrent miscarriage and immune mechanisms. Thus, unknown causes of miscarriage could be due to an immune imbalance induced by T-helper Th1/Th2/Th17 cytokines and regulatory T cells. Furthermore, these genes and mediators have long been suspected of being blood markers for the clinical diagnosis and management of miscarriage; however, more evidence is required for them to be included in medical practice and obstetric guidelines.

View all citing articles on Scopus

: The authors report no conflict of interest.

: Cite this article as: Saldarriaga W, García-Perdomo HA, Arango-Pineda J, et al. Karyotype versus genomic hybridization for the prenatal diagnosis of chromosomal abnormalities: a metaanalysis. Am J Obstet Gynecol 2015;212:330.e1-10.

View full text

ResearchObstetricsKaryotype versus genomic hybridization for the prenatal diagnosis of chromosomal abnormalities: a metaanalysis

Objective

Study Design

Results

Conclusion

Section snippets

Materials and Methods

Study selection

Characteristics of included studies

Summary of major findings

Generation of the gold standard

Diagnostico Prenat

Am J Hum Genet

Am J Hum Genet

Diagn Prenat

Eur J Med Genet

Technique modifications for reducing the risks from amniocentesis or chorionic villus sampling

Cochrane Database Syst Rev

Prenatal maternal blood screening for the detection of fetal chromosomal abnormalities: clinical importance of the rate of false positives

Invest Clin

Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

BMC Genomics

Clinical utility of chromosomal microarray analysis in invasive prenatal diagnosis

Hum Genet

Prenatal chromosomal microarray analysis in a diagnostic laboratory; experience with >1000 cases and review of the literature

Prenat Diagn

Experience with microarray-based comparative genomic hybridization for prenatal diagnosis in over 5000 pregnancies

Prenat Diagn

Clinical utility of array comparative genomic hybridization for prenatal diagnosis: a cohort study of 3171 pregnancies; editorial comment

BJOG

Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis

Ultrasound Obstet Gynecol

Research
Obstetrics
Karyotype versus genomic hybridization for the prenatal diagnosis of chromosomal abnormalities: a metaanalysis