Genomic Microarray in Fetuses With Increased Nuchal Translucency and Normal Karyotype: A Systematic Review and Meta-analysis

This systematic review was undertaken to estimate the incremental yield of detecting copy number variants (CNVs) using microarray in fetuses with increased nuchal translucency (NT) diagnosed by first-trimester ultrasound and normal karyotype (normal fluorescence in situ hybridization or quantitative fluorescence polymerase chain reaction) in order to assist clinicians in antenatal counseling. The authors performed electronic searches of databases such as PubMed, OvidMEDLINE, andWeb of Science for studies published between January 2009 and January 2015 that described CNVs in fetuses with increased NT, usually defined as 3.5mmormore, and normal karyotype. Incremental yield (risk difference) ofmicroarraywas defined as the yield over karyotyping for each prenatal series. A total of 17 studies were found to meet the inclusion criteria and were included in the meta-analysis. Pooled results from the meta-analysis of 17 studies indicate incremental yield of microarray detecting CNVs after karyotyping as 5% (95% confidence interval [CI], 2.0%-8.0%); pooled results of 16 studies indicate an incremental yield of 4% (95% CI, 2.0%-7.0%) for isolated cases of increased NT; and pooled results of 10 studies indicate an incremental yield of 7% (95% CI, 2.0%-12.0%) for cases of increased NT with associated ultrasound abnormalities. Themost common pathogenic CNVs found in the study were 22q11.2 deletion, 22q11.2 duplication, 10q26.12q26.3 deletion, and 12q21q22 deletion; size of the pathogenic CNVs ranged between 50 kb and 16 Mb. Prevalence of variants of unknown significance in all included studies were reported to range from 0.5% to 7.7%; the pooled prevalence was reported as 0.8% (95% CI, 0.4%-1.3%). The results support the use of microarray analysis in karyotypically normal fetuses with increased NT and indicate that it provides additional clinically valuable information over conventional karyotyping in 5.0% (95% CI, 2.0%-8.0%) of the fetuses (with a minimal burden of 0.8% variants of unknown significance); it may be performed as a first tier in cases with increased NT, or after the most common aneuploidies have been ruled out by normal fluorescence in situ hybridization or quantitative fluorescence polymerase chain reaction results, or after a normal karyotype. The pathogenic imbalances reported in the systematic reviewin this study indicate that themost frequently found pathogen is 22q11.2 deletion; it causes 22q11.2 microdeletion syndrome (also called DiGeorge syndrome) and accounts for 13% (5/38) of pathogenic genomic imbalances (CNVs) that are present in 5.0% of fetuses with increased NT and normal karyotype. The analysis concludes that performing microarray rather than karyotyping could lead to a decrease in undiagnosed genetic disorders in fetuses with an increased NT.