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Increased nuchal translucency: diagnostic value of RASopathy‐disorder testing

We read with interest the study of Sinajon et al.1 on chromosomal microarray analysis (CMA) and RASopathydisorder (RD) testing in fetuses with nuchal translucency (NT) thickness ≥ 3.5 mm. The authors determined the incidence of chromosomal abnormalities, submicroscopic chromosomal abnormalities and RD pathogenic variants in a total of 226 fetuses over a 3-year period. As expected, a common aneuploidy was identified in half of the cases by qualitative fluorescence polymerase chain reaction, and CMA had a 2.5% incremental yield over karyotyping, which is consistent with the literature2. RD testing yielded a detection rate of 2.9% for pathogenic variants, and NT thickness was statistically higher in cases with a positive compared to those with a negative RD result. Based on their findings, the authors proposed a clinical protocol for surveillance of pregnancies with increased fetal NT in the first trimester. However, this study raises some important questions which should be addressed. First, it is reported that the included patients with increased NT were referred over the time period from January 2013 to December 2015, while CMA was performed, using various platforms, from January 2015. When did the RD testing begin? Were the RD genes analyzed on archived fetal samples or prospectively collected samples? If the latter was the case, it would suggest that all patients with increased NT and normal karyotyping or CMA result proceeded to RD testing; however, this would be unusual because, in clinical practice, only a small proportion of patients would opt for such a test. Second, genetic diagnosis is often a time-consuming process. What was the turnaround time for RD testing? In most cases, CMA testing is the first-tier approach to examine the presence of chromosomal copy number variations in fetuses with structural anomalies or increased NT, and results are obtained at least 2 weeks after the invasive procedure. If a normal CMA result is obtained, next-generation sequencing (NGS) would usually be the next step. The minimum turnaround time of NGS in most clinical laboratories is 4 weeks. This long waiting time would frustrate the parents who are already under psychological stress due to the sonographic findings. Since the protocol proposed by the authors delivers real-time diagnoses during pregnancy, the turnaround time for RD testing is crucial for parental decision-making. Third, the proposed protocol recommends that cases with normal CMA and normal RD testing results are followed-up by early (14–16 weeks) detailed ultrasound, mid-pregnancy (18–22 weeks) detailed ultrasound and fetal echocardiography (18–20 weeks). In their study, the authors report that structural abnormalities were identified by early ultrasound in 26.1% (24/92) of cases, by mid-pregnancy ultrasound in 16.3% (15/92) and by fetal echocardiography (cardiac abnormalities) in 9.8% (9/92). Did all cases undergo all three scans? If this is the case, what was the value of the early detailed ultrasound? In this report, there were seven (8.4%) cases of termination of pregnancy and seven (8.4%) cases of intrauterine fetal death. Did all 14 cases complete the three ultrasound examinations suggested by the authors? How did the RD testing affect the pregnancy outcome in this study? Fourth, the authors concluded that the optimal NT cut-off for RD screening is 7.9 mm, based on the NT measurements in their three cases with a positive RD result (8.0 mm, 10.0 mm and 13.1 mm, respectively). However, this conclusion may not be rigorous. For instance, half of the fetuses affected by Noonan syndrome would be missed if the NT cut-off of 7.9 mm was used3. Indeed, it might be combined fetal anomalies rather than increased NT per se that is associated with RD. In this report, all three RD-positive cases had severe fetal ultrasound findings that would have likely resulted in a lethal outcome, comprising one case each of hypoplastic left ventricle, double-outlet single ventricle and hydrops. A recent study evaluated prenatal ultrasound findings of RD in a cohort of 424 fetuses over a period of 6 years, and concluded that RD testing is recommended when the fetus shows isolated increased NT ≥ 5.0 mm or when NT ≥ 3.5 mm and at least one of the following ultrasound anomalies are present: distended jugular lymphatic sacs, hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defect and renal anomaly4. Conversely, the detection rate of RD disorders is low (1.1% (1/93)) in fetuses with isolated first-trimester increased NT5. Therefore, RD testing should be reserved for cases with increased NT and additional structural defects. In this way, the cost-effectiveness of RD testing can be maximized by appropriate case selection, which, in turn, would improve detection rate. Despite our concerns about the findings of their study, we agree with the authors that genetic testing is an important investigation in patients with increased NT, especially since the findings of a molecular diagnosis might relate to both the current pregnancy and potential future ones. Although the diagnosis of genetic variants would not lead to in-utero fetal treatment, precise diagnosis during pregnancy could affect the decision about whether to proceed with the pregnancy and enable better postnatal management.