Genomic microarrays in prenatal diagnosis

Table 1 Data from the literature

Ref.	Key results
[11]	Array CGH could detect causative CNVs in children with ID, and other disabilities and congenital malformations
[12]	Feasibility of performing CGH-array for prenatal diagnosis on DNA extracted from AF cells
[13]	Evaluation of the literature up to 2009. Pathogenic CNVs or VOUS were detected in 3.6% of cases with a normal karyotype. Microarrays detected an additional 5.2% pathological CNVs or VOUS in pregnancies with fetal anomaly on ultrasound
[14-21]	Diagnostic utility of CGH- and SNP-arrays in a prenatal setting
[22]	Cohort studies, published from 2009 onwards, have demonstrated an increased detection rate over standard karyotyping ranging from 0.9% to 26.5%
[23]	Evaluation of the utility of a 1-Mb BAC and 60-K oligonucleotide array in 3171 pregnancies. The detection rate was low (0.52%) in uneventful pregnancies, but increased to 8.2% when a fetus had an abnormality on ultrasound scan
[24]	Additional information in 7.7% of cases using a SNP-array with a resolution of 150/200 kb to analyze DNA from 207 cases with fetal anomalies
[25]	Comparation of microarray with standard karyotyping in 4406 women undergoing PD for common indications over a period of 3 yr (2008-2011) The analysis identified all of the common autosomal and sex-chromosome aneuploidies and the unbalanced rearrangements detected by standard karyotyping in the 4282 non mosaic samples. Microdeletions or duplications of clinical significance were found in 96 of 3822 fetal samples with normal karyotypes (2.5%), including 6.0% of cases in which fetal anomalies were detected on ultrasonography. There were 94 copy-number variants of uncertain clinical significance that required further evaluation. The pathogenicity of 1.5% of CNVs remained uncertain
[26]	Exploration of the utility of microarray analysis in groups of pregnancies with a priori low risk for detection of submicroscopic chromosome abnormalities. A total of 3000 prenatal samples were processed in parallel using both microarray and conventional karyotyping. Samples were processed using a BAC platform with a resolution of about 1 Mb across the genome and about 100 kb in 139 regions associated with constitutional disorders. The percentage of detection was 0.5% (6/1118) in advanced maternal age and 0.7% (11/1674) in parental anxiety. No genetic imbalances were detected in any of the cases sampled for an abnormal maternal serum screening, nor for a family history of a genetic condition or chromosomal abnormality. A total of 24 (0.8%) fetal conditions would have remained undiagnosed if only a standard karyotype had been performed. 17 (0.6%) of such findings would have otherwise been overlooked if CMA was offered only to high risk pregnancies
[27]	Study on 5003 prospective cases received for a variety of indications. The overall detection rate of clinically significant CNAs was 5.3%. Detection rates were 6.5% and 8.2% for cases referred with abnormal ultrasounds and fetal demise, respectively. The overall rate of findings with VOUS was 4.2% but would reduce to 0.39% if only de novo CNAs were considered. In cases with known chromosomal rearrangements in the fetus or parent, 41.1% showed CNAs related to the rearrangements, whereas 1.3% showed clinically significant CNAs unrelated to the karyotype. 71% of the clinically significant CNAs found by microarray were below the resolution of conventional karyotyping of fetal chromosomes
[28]	Evaluation of a multicentric collection of a 1-yr series of fetal samples with indication for prenatal invasive sampling simultaneously using three screening methodologies: (1) karyotype and QF-PCR; (2) two panels of MLPA; and (3) microarray-based analysis with a targeted BAC microarray. On a total of 900 samples, technical performance was excellent for karyotype, QF-PCR, and GMA (about 1% failure rate) but relatively poor for MLPA (10% failure). Mean turn-around time was 7 d for microarray or MLPA, 25 d for karyotype and 2 d for QF-PCR, with similar combined costs for each approach. A total of 57 clinically significant chromosomal aberrations were found (6.3%), with microarray yielding the highest detection rate (32% above other methods). The identification of VOUS (17, 1.9%) tripled that of karyotype and MLPA, but most alterations could be classified as likely benign after proving they were inherited
[29]	Evaluation of the results of prenatal microarray analysis on > 1000 fetal samples referred for testing and comparation of these data to published reports. Clinically significant CNVs were observed in 85/1115 cases (7.6%). Eighteen of the 1115 cases had VOUS (1.6%). Indications yielding the most clinically significant findings were abnormal karyotype/FISH (26/61, 42.6%), family history of chromosomal abnormality (13/137, 9.5%), abnormal ultrasound (38/410, 9.3%), abnormal serum screening (2/37, 5.4%) and advanced maternal age (5/394, 1.3%). Of 1075 cases having no previously known cytogenetic abnormality or family history, 18 (1.7%) had clinically significant genomic changes undetectable by conventional prenatal chromosome analysis
[30-33]	Papers reporting experience on a small number of samples and addressing the main issues in this field
[34]	Prospective cohort study of 243 women undergoing microarray testing alongside karyotyping when a structural abnormality was detected on prenatal ultrasound scan and review and meta-analysis of the literature. The collective number of samples analysed were 17113. The overall agreement between the two tests was 93.4% (95%CI: 90.4%-96.5%). The results obtained in attempting to calculate the rate of microarray detection over karyotyping were highly heterogeneous, ranging from 0.4% to 50%. When the indication was structural abnormality seen on ultrasound scan the detection rate over karyotyping was 10% (95%CI: 8%-13%). A sub analysis performed using cohorts published between 2011 and 2012 showed a lower detection rate (7%, 95%CI: 5%-10%). The authors suggest that GMA could have a higher detection rate not just in cases of abnormal scan findings but also with other indications for invasive testing, and conclude that it is likely that microarray testing will replace karyotyping in high risk pregnancies

BAC: Bacterial artificial chromosomes; CNAs: Copy number alterations; CGH-arrays: Comparative genomic hybridization-based arrays; CMA: Chromosomal microarray analysis; CNVs: Copy number variations; MLPA: Multiplex ligation-dependent probe amplification; PD: Prenatal diagnosis; QF-PCR: Quantitative fluorescent polymerase chain reaction; SNP-arrays: Single nucleotide polymorphism-based arrays; VOUS: Variants of uncertain (unknown) significance; ID: Intellectual disabilities.