A novel variant of the POLR3A gene in a patient with hypomyelinating POLR3-related leukodystrophy

Background: Hypomyelinating POLR3-related leukodystrophy is a group of rare neurological diseases characterized by degeneration of the white matter of the brain with different combinations of major clinical findings. Here we report the first Korean POLR3-related leukodystrophy caused by bi-allelic POLR3A c.1771-6C > G and novel c.1650_1661del variants. Methods: An 18-month-old girl was admitted for evaluation of a seizure-like activity with spasticity that affected her entire body. She showed dental abnormalities, but not suspicious facial dysmorphism. She was in a bed-ridden state with severe cognitive impairments and episodes of dystonic posturing for 1–2 min. Trio exome sequencing (ES) was performed to determine the potential genetic cause of severe developmental delay with leukodystrophy in our proband. Results: Trio ES revealed that bi-allelic POLR3A deleterious variants, c.1650_1661del of the exon 13, and c.1771-6C > G of the intron 13 were best candidate as causes of hypomyelinating POLR3-related leukodystrophy. Sanger sequencing confirmed the genetic origin of these POLR3A deleterious variants as autosomal recessive hereditary transmission. Conclusion: Our report provides additional evidence for a phenotypic continuum of hypomyelinating POLR3-related leukodystrophy caused by bi-allelic POLR3A variants. Further genetic studies are required to understand underlying pleiotropic effects of different POLR3A variants.