Meera Sridhar Shah1, Cengiz Cinnioglu2, Melissa Maisenbacher3, Ioanna Comstock4, Jonathan Kort4, Ruth Bunker Lathi4. 1. Stanford University Reproductive Health and Fertility Center, Palo Alto, California. Electronic address: shahm@stanford.edu. 2. Ivigen, Inc., Miami, Florida. 3. Natera, Inc., San Carlos, California. 4. Stanford University Reproductive Health and Fertility Center, Palo Alto, California.
Abstract
OBJECTIVE: To compare chromosome testing of miscarriage specimens between traditional cytogenetic analysis and molecular karyotyping using single nucleotide polymorphism microarrays (SNP) and array comparative genomic hybridization (aCGH). DESIGN: Prospective blinded cohort study. SETTING: University-based practice. PATIENT(S): Women undergoing dilation and curettage for first-trimester miscarriage between March 2014 and December 2015. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Chromosome analysis from chorionic villi separated equally and submitted for cytogenetics, SNP microarray, and aCGH testing. RESULT(S): Sixty samples were analyzed, of which 47 (78%) were chromosomally abnormal. A correct call was defined when a result was concordant with at least one other testing platform. The correct call rate was 85%, 93%, and 85% using cytogenetics, SNP array, and aCGH, respectively. We found a 33% overall discordance rate between results. Discordances were due to maternal cell contamination, balanced chromosome rearrangements, polyploidy, and placental mosaicism. Mosaicism was detected in 18% of all samples. Growth failure occurred in four samples sent to cytogenetics, of which three were chromosomally abnormal by molecular testing. CONCLUSION(S): This study demonstrates the many technical limitations of the three testing modalities. Our rates of maternal cell contamination were low, but it is important to note that this is a commonly reported limitation of cytogenetics. Given the similar overall performance of the three testing modalities, providers may choose a method based on individual availability and consideration of limitations as it applies to each clinical scenario. The unexpected high rate of placental mosaicism warrants further investigation.
OBJECTIVE: To compare chromosome testing of miscarriage specimens between traditional cytogenetic analysis and molecular karyotyping using single nucleotide polymorphism microarrays (SNP) and array comparative genomic hybridization (aCGH). DESIGN: Prospective blinded cohort study. SETTING: University-based practice. PATIENT(S): Women undergoing dilation and curettage for first-trimester miscarriage between March 2014 and December 2015. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Chromosome analysis from chorionic villi separated equally and submitted for cytogenetics, SNP microarray, and aCGH testing. RESULT(S): Sixty samples were analyzed, of which 47 (78%) were chromosomally abnormal. A correct call was defined when a result was concordant with at least one other testing platform. The correct call rate was 85%, 93%, and 85% using cytogenetics, SNP array, and aCGH, respectively. We found a 33% overall discordance rate between results. Discordances were due to maternal cell contamination, balanced chromosome rearrangements, polyploidy, and placental mosaicism. Mosaicism was detected in 18% of all samples. Growth failure occurred in four samples sent to cytogenetics, of which three were chromosomally abnormal by molecular testing. CONCLUSION(S): This study demonstrates the many technical limitations of the three testing modalities. Our rates of maternal cell contamination were low, but it is important to note that this is a commonly reported limitation of cytogenetics. Given the similar overall performance of the three testing modalities, providers may choose a method based on individual availability and consideration of limitations as it applies to each clinical scenario. The unexpected high rate of placental mosaicism warrants further investigation.