Titel: Increased nuchal translucency (NT). Can we do more? Prenatal trio exome sequencing revealed unexpected findings in fetuses with increased NT
ID: P-ClinG-054
Art: Postertalk
Redezeit: 2 min
Session: Poster Session
ClinG 2

Referent: Heinz Gabriel (Tuebingen/DE)

Abstract - Text


It is estimated that ultrasound diagnosis in the first trimester allows for the detection of approx. half of all major structural anomalies, including those of the central nervous system, cardiovascular system and gastrointestinal system. Another aspect of fetal ultrasound diagnosis is to detect so called "soft markers", which are indicative of chromosomal abnormalities. One of these soft markers is nuchal translucency (NT) which is observed as a subcutaneous edema in the nuchal region during the late first trimester. Increased NT is associated with a spectrum of structural anomalies. Mostly, NT measurement is offered as part of first-trimester screening for chromosomal abnormalities (e.g. trisomies). It is well established that about 20% of fetuses with increased NT will have a chromosomal abnormality. Microarray provides an additional diagnostic yield of about 5%.RASopathy disorders/Noonan syndrome is considered the most frequently reported syndrome associated with increased NT. With the introduction of next-generation-sequencing (NGS), prenatal panel testing for Noonan syndrome genes is nowadays widely offered in cases with increased NT. Aside from these Noonan syndrome genes, there are only a limited number of gene for which increased NT is documented.

Whole exome sequencing (WES) and trio exome sequencing is becoming the first-tier diagnostic test for many unclear genetic conditions. Recently, we have shown that trio-exome-sequencing is also a powerful diagnostic tool in prenatal testing. Here, we performed prenatal trio exome sequencing in cases with increased NT/Hygroma.


A cohort of 143 fetuses with increased NT/hygroma seen during routine ultrasonography were analysed by trio exome sequencing. Only likely pathogenic and pathogenic variants were reported. The mean turn-around-time (TAT) was 18 days with a shortest TAT of 5 days.


Among the 143 tested fetuses, we detected pathogenic or likely pathogenic variants in 40 cases (28%). Noonan syndrome genes were found in 7 cases (incl. 4x PTPN11). In 4 cases we detected a causative variant in genes which are known to be associated with increased NT. Another 4 cases showed pathogenic microdeletions or -duplications. In all other cases (25x) pathogenic variants were found in genes which are not to be known to be associated with increased NT so far.


Our data clearly demonstrate that prenatal testing should not be limited to structural or numerical chromosomal aberrations, or RASopathies, in cases with [AP1] increased NT. Increased NT can be found in a wide range of syndromic conditions and increased NT might be one of the earliest detectable phenotypic features in the first trimester. Therefore, increased NT is a significant marker for wide range of genetic disorders. We have shown the value of trio exome sequencing for the prenatal genetic diagnosis of fetuses with increased NT, and trio exome testing should be the standard approach for fetuses with increased NT.