Detection of fetal trisomy 13, 18, and 21 via maternal plasma analysis

see DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study

Next-generation sequencing (NGS) is realizing its promise rapidly in the context of clinical medicine, and one of the first routine applications of such technology will probably be for screening in the prenatal setting. Recently, GIM brought you a study demonstrating the feasibility of diagnosing Down syndrome through analysis of fetal DNA circulating in maternal plasma early in pregnancy. In this issue, the same group expands this technique to the other common trisomies, 13 and 18.

Sixty-two trisomy 18 and 12 trisomy 13 pregnancies were selected from a cohort of 4,664 pregnancies and, along with matched euploid controls, were tested using a laboratory-developed NGS approach. Among the 99.1% of samples interpreted (1,971/1,988), the observed trisomy 18 and trisomy 13 detection rates were 100% (59/59) and 91.7% (11/12) at false-positive rates of 0.28% and 0.97%, respectively. If z-score cutoffs for trisomy 18 and trisomy 13 were raised slightly, the overall false-positive rates for the three aneuploidies could be as low as 0.1% (2/1,688) at an overall detection rate of 98.9% (280/283) for common aneuploidies. An independent academic laboratory confirmed performance in a subset.

Thus, in high-risk pregnancies, sequencing circulating cell-free DNA detects nearly all cases of Down syndrome, trisomy 18, and trisomy 13, at a low false-positive rate, potentially reducing invasive diagnostic procedures and related fetal losses by 95%.

Impressive laboratory performance in the diagnosis of fragile X syndrome

see Molecular genetic testing for fragile X syndrome: laboratory performance on the College of American Pathologists proficiency surveys (2001–2009)

A great deal rides on the accuracy and reliability of genetic testing. The stakes are high and the task difficult, especially when considering complex tests such as those used to detect trinucleotide repeat expansion for the diagnosis of fragile X syndrome. Weck et al. report on almost a decade of laboratory performance with respect to diagnosis of this condition. Individual laboratory responses were analyzed for accuracy of genotype determination (normal, gray zone, premutation, or full mutation) and size analysis of the FMR1 trinucleotide repeat region. Overall, the results are encouraging, with laboratories demonstrating analytical sensitivity of 99% and 96% for detection of full mutations associated with fragile X syndrome in males and females, respectively. For premutation detection, analytical sensitivity was 98% and analytical specificity was 99.9%.

The study concludes that molecular genetic testing for fragile X syndrome has demonstrated excellent sensitivity and specificity among laboratories participating in annual proficiency surveys. Also, encouragingly, the accuracy of allele sizing significantly improved over the study period.