Propionic Acidemia (PA) is an inborn error of metabolism caused by variants in the PCCA or PCCB genes, leading to mitochondrial accumulation of propionyl-CoA and its by-products. Here, we report a 2 year-old Egyptian boy with PA who was born to consanguineous parents. Biochemical analysis was performed using tandem mass spectrometry (MS/MS) on the patient's dried blood spots (DBS) followed by urine examination of amino acids using gas chromatography/mass spectrometry (GC/MS). Molecular genetic analysis was carried out using whole-exome sequencing (WES). The PCCA gene sequencing revealed a novel homozygous missense variant affecting the locus (chr13:100962160) of exon 16 of the PCCA gene, resulting in the substitution of the amino acid arginine with proline at site 476 (p.Arg476Pro). Computational analysis revealed that the novel variant might be pathogenic and attributed to decrease the stability and also has an effect on the biotin carboxylase c-terminal domain of the propionyl carboxylase enzyme. The physicochemical properties analysis using NCBI amino acid explorer study revealed restrictions in the side chain and loss of hydrogen bonds due to the variant. On the structural level, the loss of beta-sheet was observed due to the variant proline, which has further led to the loss of surrounding interactions. This loss of beta-sheet and the surrounding interactions might serve the purpose of the structural stability changes. The current study demonstrates that a combination of whole-exome sequencing (WES) and computational analysis are potent tools for validation of diagnosis and classification of disease-causing variants.

丙酸血症（PA）是PCCA或PCCB基因变异导致的先天性代谢错误，导致丙酰辅酶A及其副产物的线粒体积累。在这里，我们报告了一个2岁的埃及男孩，患有PA，是由近亲的父母所生。使用串联质谱（MS / MS）对患者的干血斑（DBS）进行生化分析，然后使用气相色谱/质谱（GC / MS）对氨基酸进行尿液检查。使用全外显子测序（WES）进行分子遗传分析。的PCCA基因测序揭示影响基因座的纯合新颖错义变异体（CHR 13：100962160）的外显子16的PCCA基因，导致在位点476（p.Arg476Pro）用脯氨酸取代氨基酸精氨酸。计算分析表明，该新变体可能是致病的，并归因于其稳定性的降低，并且还对丙酰羧化酶的生物素羧化酶c-末端结构域产生影响。使用NCBI氨基酸资源管理器研究的理化性质分析显示，由于变异，限制了侧链和氢键的丢失。在结构水平上，由于脯氨酸的变异，导致β-折叠的丢失，这进一步导致周围相互作用的丧失。β-sheet和周围的相互作用的这种损失可能达到结构稳定性变化的目的。