A uniparental isodisomy event introducing homozygous pathogenic variants drives a multisystem metabolic disorder

Uniparental isodisomy (UPiD) is a rare genetic event that occurs when two identical copies of a single chromosome are inherited from one parent. Here we report a patient with a severe, multisystem metabolic disorder who inherited two copies of Chromosome 12 from her father. He was a heterozygous carrier of a variant in the muscle-specific enzyme 6-phosphofructokinase (PFKM) gene and of a truncating variant in the pseudouridine synthase 1 (PUS1) gene (both on Chromosome 12), resulting in a homozygous state of these mutations in his daughter. The PFKM gene functions in glycolysis and is linked to Tarui syndrome. The PUS1 gene functions in mitochondrial tRNA processing and is linked to myopathy, lactic acidosis, and sideroblastic anemia (MLASA). Analysis of human dermal fibroblasts, which do not express PFKM, revealed a loss of PUS1 mRNA and PUS1 protein only in the patient cells compared to healthy controls. The patient cells also revealed a reduction of the mitochondrial-encoded protein MTCO1, whereas levels of the nuclear-encoded SDHA remained unchanged, suggesting a specific impairment of mitochondrial translation. Further destabilization of these cells is suggested by the altered levels of BAX, BCL-2, and TP53 proteins, alterations that become augmented upon exposure of the cells to DNA damage. The results illustrate the efficacy of UPiD events to reveal rare pathogenic variants in human disease and demonstrate how these events can lead to cellular destabilization.