Investigating the structural impacts of a novel missense variant identified with whole exome sequencing in an Egyptian patient with propionic acidemia

Ali Zaki Ibrahim; D Thirumal Kumar; Taghreed Abunada; Salma Younes; C George Priya Doss; Osama K Zaki; Hatem Zayed

doi:10.1016/j.ymgmr.2020.100645

Investigating the structural impacts of a novel missense variant identified with whole exome sequencing in an Egyptian patient with propionic acidemia

Mol Genet Metab Rep. 2020 Sep 17:25:100645. doi: 10.1016/j.ymgmr.2020.100645. eCollection 2020 Dec.

Authors

Ali Zaki Ibrahim¹, D Thirumal Kumar², Taghreed Abunada³, Salma Younes³, C George Priya Doss², Osama K Zaki⁴, Hatem Zayed³

Affiliations

¹ Faculty of Medicine, Ain Shams University, Cairo, Egypt.
² School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
³ Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar.
⁴ Medical Genetics Unit, Pediatric Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Abstract

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.

Keywords: Computational analysis; Genotype-phenotype correlation; Next-generation sequencing; PCCA gene; Propionic acidemia (PA).