Maternal mixed UPD3 and a homozygous PLXNA1 c.2497G>C variant in a fetus with severe anomalies.

Background: Non-invasive prenatal testing (NIPT) is widely used for screening common fetal aneuploidies such as trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13). However, its utility in detecting trisomy 3 (T3) has been rarely reported. Furthermore, uniparental disomy (UPD) involving chromosome 3 is a rare genetic condition with potential phenotypic consequences. Methods: NIPT indicated a high risk for fetal T3. This finding was further investigated using copy number variation (CNV) analysis via trio-based chromosomal microarray analysis (trio-CMA). Subsequent trio-based whole-genome sequencing (trio-WGS) identified a homozygous variant in PLXNA1 associated with a putative autosomal recessive disorder in the fetus. The detected variant was validated by Sanger sequencing in the parents. Results: NIPT revealed a fetal Conclusions: While NIPT can signal a high risk for rare aneuploidies, definitive diagnosis requires invasive prenatal testing. Discrepancies between NIPT and fetal tissue analyses may arise from confined placental mosaicism (CPM). We propose a model in which nondisjunction of chromosome 3 during germ cell formation led to trisomy, followed by a postzygotic self-correction event, resulting in mixed maternal UPD3 and increased risk of autosomal recessive disorders.