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.

Conclusions: 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.