Caution urged in reporting noninvasive prenatal screening results to patients

see Discordant noninvasive prenatal testing and cytogenetic results: a study of 109 consecutive cases

Prospective parents who are told there is a 99% chance their fetus is affected by trisomy 18 are likely to react very differently than those being told that the actual likelihood of trisomy 18 is less than 60%, based solely on the result of noninvasive prenatal testing (NIPT). A clinician not savvy in basic statistics could perhaps be excused for assuming a test specificity of 99.9% means the test is nearly foolproof. But that’s not the case if the condition in question is relatively rare. This issue is of particular importance for NIPT results, which, because of the relatively low prevalence of the conditions sought by the test, still must be confirmed by direct cytogenetic studies. The critical difference between test specificity and the more important positive predictive value (PPV) is illustrated in the report in this issue by physician–scientists at the Quest Diagnostics Nichols Institute. The research team examined the results of cytogenetic follow-up tests ordered after a positive NIPT for the trisomy 21, 18, and 13 in 109 consecutive specimens from several NIPT providers in California. They found a true-positive rate of 93% for trisomy 21, 64% for trisomy 18, and only 44% for trisomy 13. The authors explain that the low figures can be accounted for by the statistical prevalence of the abnormalities in the women undergoing testing. Even if the test specificity were 99.9%, the PPV for diagnosing these three trisomies would be much lower, as borne out by the figures presented here. The authors urge education of clinicians about the important difference between published specificities and the more important statistic of PPV, particularly in light of recent data suggesting that positive NIPT results are in some cases not being followed up with cytogenetic studies. The authors stress that NIPT is a screening test, not a substitute for invasive prenatal diagnosis, and thus should properly be referred to as NIPS. —Karyn Hede, News Editor

Study links subset of mutations with aortic events in marfan syndrome patients

see Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events

Among the many possible mutations in the fibrillin-1 (FBN1) gene causing Marfan syndrome, the subset comprising truncations and splicing disruptions may be associated with more severe aortic events. In this issue, Baudhuin et al., of the Mayo Clinic, Rochester, Minnesota, present data suggesting that truncating and splicing events are associated with early aortic events such as aortic dissection and aortic surgery. The study examined the clinical records for 179 consecutive Marfan syndrome patients referred to the Mayo Clinic over a four-year period. The findings contradict the current understanding that patients with these mutations actually have a milder course of disease. The authors speculate that clinicians may have thought these patients are less affected because they often have fewer outward manifestations of the disease as judged by the generally accepted clinical criteria (Ghent nosology criteria). By contrast, the current study showed that of patients who had an early aortic event, all (12/12, <30 years) or nearly all (20/21, <40 years) had a truncating or splicing variant. In addition, the researchers observed that aortic dissection or surgery occurred at a younger age in patients with a truncating or splicing variant (median age, 29 years) as compared with other types of mutations (51 years). The findings suggest that Marfan syndrome patients with FBN1 truncating and splicing variants should be followed closely to prevent potentially catastrophic aortic events. —Karyn Hede, News Editor