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

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.

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.

NIPT revealed a fetal Z-score (27.22) for T3. Trio-CMA ruled out T3 but confirmed mixed maternal UPD3. Trio-WGS identified a homozygous PLXNA1 variant (NM_032242.3:c.2497G>C, p.Ala833Pro) in the fetus, inherited from the heterozygous mother. The observed severe fetal phenotype was partial consistent with the molecular findings of mixed UPD3 and the homozygous PLXNA1 variant, indicating that this variant may represent a potential pathogenic cause.

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.