Identification and characterization of novel compound variants in SLC25A26 associated with combined oxidative phosphorylation deficiency 28.

• Novel variants of SLC25A26 caused COXPD28. • Genotype-phenotype correlation of COXPD28. Summary of SLC25A26 variants. Combined oxidative phosphorylation deficiency 28 (COXPD28) is associated with mitochondrial dysfunction caused by mutations in SLC25A26 , the gene which encodes the mitochondrial S-adenosylmethionine carrier (SAMC) that responsible for the transport of S-adenosylmethionine (SAM) into the mitochondria. To identify and characterize pathogenic variants of SLC25A26 in a Chinese pedigree, provide a basis for clinical diagnosis and genetic counseling. We conducted a systematic analysis of the clinical characteristics of a female with COXPD28. Whole-exome and mitochondrial genome sequencing was applied for the genetic analysis, together with bioinformatic analysis of predicted consequences of the identified variant. A homotrimer model was built to visualize the affected region and predict possible outcomes of this mutation. Then a literature review was performed by online searching all cases reported with COXPD28. The novel compound heterozygous SLC25A26 variants (c.34G > C, p.A12P; c.197C > A; p.A66E) were identified in a Chinese patient with COXPD28. These two variants are located in the transmembrane region 1 and transmembrane region 2, respectively. As a member of the mitochondrial carrier family, the transmembrane region of SAMC is highly conserved. The variants were predicted to be pathogenic by in silico analysis and lead to a change in the protein structure of SAMC. And the change of the SAMC structure may lead to insufficient methylation and cause disease by affecting the SAM transport. The variants in this region probably resulted in a variable loss of mitochondrial SAMC transport function and cause the COXPD28. This study that further refine genotype-phenotype associations can provide disease prognosis with a basis and families with reproductive planning options. [ABSTRACT FROM AUTHOR]