Identification of novel compound heterozygote variants in the PCCB gene in a fetus with undetectable fetal phenotype

Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by functional deficiency of propionyl-CoA carboxylase, clinically characterized by life-threatening ketoacidosis, hyperammonemia, and multiorgan dysfunction. Due to its nonspecific clinical manifestations, PA is frequently misdiagnosed or only identified during severe metabolic crises. This study reports a Chinese family with a history of offspring affected by PA. Through whole-exome sequencing and Sanger validation of fetal amniotic fluid and parental peripheral blood samples, two novel compound heterozygous variants in the PCCB gene were identified in the fetus, initially classified as variants of uncertain significance (VUS) per ACMG guidelines. Subsequent functional studies and amniotic fluid metabolomic analyses were performed. The results demonstrated that the paternal PCCB c.366_372 + 7del variant caused exon 3 skipping(p.Phe102_Gln124del) or exon 2–3 skipping (p.Gly62_Gln124del), while the maternal c.183 + 6T > G variant resulted in intron 1 retention (p.Gly62Valfs*10), both leading to protein truncation and aberrant mRNA splicing. Metabolomic analysis demonstrated significantly elevated C3 levels and an increased C3/C2 ratio, consistent with PA diagnosis. These novel PCCB splicing variants expand the mutational spectrum of PA and demonstrate the clinical utility of integrated genomic-metabolomic analysis for prenatal diagnosis and genetic counseling in high-risk PA families.