Contingent cfDNA Screening Implementation: Increasing Diagnostic Accuracy and Reducing Invasive Testing - 6 Years' Results in a Single Center.

OBJECTIVES: Universal screening for trisomy using cell-free DNA (cfDNA) has proven to be more effective than combined test, but it is not cost efficient currently. Contingent cfDNA screening on the results of the first-trimester combined test can improve the detection rate of the combined test and reduce the number of invasive tests at a lower cost than universal screening. In 2018, a contingent screening program was implemented in the community of Castilla y Leon (Spain). This study aims to compare the results achieved in Salamanca University Hospital during the first 3 years of contingent screening (2018-2020) with those of the previous 3 years (2015-2017) to assess the changes in the trisomy detection rate and the number of invasive tests. METHODS: A total of 9,903 singleton pregnancies without malformations nor nuchal translucency >p99 were included. 5,165 patients underwent combined screening and 4,738 had contingent screening based on the combined test risk. In the combined test group, women were offered an invasive test if the risk was ≥1:270, while risks under 1:270 were considered low risks, and no further testing was offered. In the contingent screening group, invasive testing was offered if the risk was ≥1:100 (≥1:50 from 2020 onwards), while cfDNA was offered if the combined test risk was between 1:100 and 1:1,000 (1:50-1:1,000 from 2020 onwards). When risk was <1:1,000, no further testing was offered. Aneuploidies detected by cfDNA were confirmed by invasive diagnostic testing. RESULTS: There were 33 cases of trisomy 21 (T21) throughout the 6 years of study. Four cases had low/intermediate risks and were spotted by cfDNA. Risk >1:1,000 threshold for contingent test detected 100% T21. There was a false-positive result for trisomy 13. There were no false-negative results. "No-call" cfDNA results were minimized by repeating blood collection 2 weeks later, as fetal fraction (FF) was doubled. Invasive testing had a drop rate of 84% after contingent screening implementation. DISCUSSION: The implementation of population-based contingent screening significantly reduces the number of invasive tests without lowering diagnostic accuracy. To achieve the maximum efficiency of the program, it is important to know the best cut-offs according to the population where the program is to be implemented. The number of uninformative results due to low FF can be reduced by repeating the test 2 weeks after the initial extraction: this increases the FF to twice the initial one, achieving informative results and avoiding unnecessary invasive tests.

Ductus Venosus Agenesis as a Marker of Pallister-Killian Syndrome.

The ductus venosus (DV) is a shunt that allows the direct flow of well-oxygenated blood from the umbilical vein (UV) to the coronary and cerebral circulation through the foramen ovale. Its agenesis has been associated with chromosomal abnormalities and rare genetic syndromes, structural defects, intrauterine growth restriction (IUGR) and even antepartum fetal demise. Pallister-Killian Syndrome (PKS) is a rare sporadic disorder with specific tissue mosaic distribution of an extra 12p isochromosome (i(12p)). Its main clinical features are moderate to severe intellectual disability/neuromotor delay, skin pigmentation abnormalities, typical facial appearance, variable association with multiple congenital malformations and epilepsy. Though prenatal findings (including congenital diaphragmatic hernia, ventriculomegaly, congenital heart disease, polyhydramnios, and rhizomelic shortening) have been described in literature, prenatal diagnosis is difficult as there are no associated identification signs no distinctive or pathognomonic signs, and some of these malformations are hard to identify prenatally. The tissue mosaicism linked to this syndrome and the decrease of the abnormal clone carrier of the i(p12) after successive trypsinizations of cultured cells makes the diagnosis even more challenging. We present the case of a 27.5 weeks pregnant woman with a fetal ductus venosus agenesis (DVA) as the main guide marker. To our knowledge this is the first case published in literature reporting a DVA as a guide sign to diagnose a complex condition as Pallister-Killian syndrome. We also underscore the key role of new genetic techniques as microarrays to avoid misdiagnosis when only a subtle sonographic sign is present in complex conditions like this.