Combinations of exonic deletions and rare mutations lead to misdiagnosis of propionic acidemia

Abstract Propionic acidemia (PA) is an inborn metabolic error characterized by the accumulation of propionic acid due to deficiency of propionyl-CoA carboxylase (PCC). In this study, we present an intractable case with PCC activity defects. Although next-generation sequencing was applied twice to test genetic defects of the patients, no pathogenic mutations of a metabolic disease gene were identified. Mutations related to the disease were screened in prenatal diagnosis, but the mother still gave birth to an unhealthy neonate. We analyzed the second sequencing data and found that a novel synonymous PCCA mutation c.1746 G>C (p.S582S), which leads to an exon 19 skip, was screened out. Furthermore, a deletion mutation covering exon 3 and exon 4 of the PCCA gene was identified using q-PCR and DNA breakpoint test. Both of these can result in the loss of PCCA protein function. The finding expands the mutation spectrum of the PCCA gene and indicates that another technology such as cDNA analysis, multiplex ligation-dependent probe amplification (MLPA), or long-read whole-genome sequencing should be considered to improve the detection rates of special cases.