Prenatal ultrasound findings of rasopathies in a cohort of 424 fetuses: update on genetic testing in the NGS era

Abstract

BackgroundThis study evaluates 6 years of prenatal rasopathy testing in the Netherlands, updates on previous data and gives recommendations for prenatal rasopathy testing.Methods424 fetal samples, sent in for prenatal rasopathy testing in 2011–2016, were collected. Cohort 1 included 231 samples that were sequenced for 1–5 rasopathy genes. Cohort 2 included 193 samples that were analysed with a 14-gene next generation sequencing (NGS) panel. For all mutation-positive samples in both cohorts, the referring physician provided detailed ultrasound findings and postnatal follow-up. For 168 mutation-negative samples in cohort 2, solely clinical information on the requisition form was collected.ResultsIn total, 40 (likely) pathogenic variants were detected (9.4%). All fetuses showed a variable degree of involvement of prenatal findings: increased nuchal translucency (NT)/cystic hygroma, distended jugular lymph sacs (JLS), hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies. An increased NT was the most common finding. Eight fetuses showed solely an increased NT/cystic hygroma, which were all larger than 5.5 mm. Ascites and renal anomalies appeared to be poor predictors of pathogenic outcome.ConclusionFetuses with a rasopathy show in general multiple ultrasound findings. The larger the NT and the longer it persists, the more likely it is to find a pathogenic variant. Rasopathy testing is recommended when the fetus shows an isolated increased NT ≥5.0 mm or when NT of ≥3.5 mm and at least one of the following ultrasound anomalies is present: distended JLS, hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies.

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

“…Our study confirms the strong association between nuchal fluid accumulation and RASopathies, of which Noonan syndrome is the most common . This group represented 52% of the single gene disorders diagnosed in the cohort.…”

“…Of note is that all the fetuses with RASopathies had all NT larger than 3.1 mm. in a recent study RASopathy analysis is recommended in all cases of NT ≥5mm, even in the absence of additional markers …”

Reply

“…An active area of research for our group is reviewing the literature to identify an optimal NT value for making a diagnosis of RD. We read the article of Stuurman et al with particular interest given the large size of their study cohort 6 . The suggestion of using two different NT cut-offs based on the presence of ultrasound findings is interesting and certainly requires further review.…”

“…We read the article of Stuurman et al . with particular interest given the large size of their study cohort. The suggestion of using two different NT cut‐offs based on the presence of ultrasound findings is interesting and certainly requires further review.…”

Increased nuchal translucency: diagnostic value of RASopathy‐disorder testing

“…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 anomaly. Conversely, the detection rate of RD disorders is low (1.1% (1/93)) in fetuses with isolated first‐trimester increased NT.…”