Jun 16 - Beyond the Common Aneuploidies: Optimal Diagnostic Workup and Counseling Following Positive cfDNA Screening OnDemand-Beyond the Common Aneuploidies

Video Transcription

Video Summary

This ACMG webinar reviewed optimal diagnostic workup and counseling after positive cell-free DNA (cfDNA) screening beyond the common trisomies. The presenters explained how cfDNA is derived from maternal and placental DNA, how next-generation sequencing or SNP-based methods are used, and why fetal fraction, assay design, and laboratory reporting details matter.

Three main case types were discussed:

1. <strong>Rare autosomal trisomies (trisomy 16):</strong>  
   A positive cfDNA result may reflect full fetal trisomy, confined placental mosaicism, mosaic fetal involvement, or technical/maternal causes. Because placental mosaicism is common, <strong>amniocentesis</strong> is usually preferred over CVS when ultrasound is normal. Even if fetal testing is normal, pregnancies may still need close monitoring for growth restriction and other complications. The case also highlighted <strong>trisomic rescue</strong> and the possibility of <strong>uniparental disomy (UPD)</strong>.

2. <strong>Microdeletions (22q11.2 deletion):</strong>  
   cfDNA screening for small CNVs has lower positive predictive value than for common aneuploidies. Confirmatory testing with <strong>amniocentesis and chromosomal microarray</strong> is important. The case emphasized that different cfDNA platforms can yield different results, and that copy-neutral regions of homozygosity may suggest UPD.

3. <strong>Sex chromosome aneuploidy (monosomy X):</strong>  
   Monosomy X has a substantial false-positive rate due to placental mosaicism and maternal mosaicism. When fetal ultrasound is abnormal, invasive testing is recommended; otherwise amniocentesis or postnatal testing may be more appropriate. One case revealed unexpected <strong>maternal mosaic Turner syndrome</strong>, underscoring the need to consider maternal origins of results.

Overall, the session stressed multidisciplinary care, careful counseling about limitations and predictive value, and choosing confirmatory testing based on the suspected abnormality and tissue source.

Keywords

cfDNA screening

rare autosomal trisomy

trisomy 16

confined placental mosaicism

amniocentesis

22q11.2 deletion

chromosomal microarray

monosomy X

maternal mosaic Turner syndrome

uniparental disomy