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.

中文翻译：

---

外显子缺失和罕见突变的组合导致丙酸血症的误诊。

丙酸血症（PA）是一种先天性代谢错误，其特征在于由于丙酰CoA羧化酶（PCC）的缺乏而导致丙酸的积累。在这项研究中，我们提出了PCC活动缺陷的棘手案例。尽管下一代测序两次用于测试患者的遗传缺陷，但未发现代谢疾病基因的致病突变。在产前诊断中筛查了与该疾病有关的突变，但母亲仍生下了不健康的新生儿。我们分析了第二个测序数据，发现筛选出一个新的同义PCCA突变c.1746 G> C（p.S582S），该突变导致外显子19跳跃。此外，使用q-PCR和DNA断裂点测试鉴定了覆盖PCCA基因的外显子3和外显子4的缺失突变。两者都可能导致PCCA蛋白功能丧失。这一发现扩大了PCCA基因的突变谱，并表明应考虑使用另一种技术，例如cDNA分析，多重连接依赖探针扩增（MLPA）或长期阅读的全基因组测序，以提高特殊病例的检出率。