The association of POLR3K variants with autosomal recessive hypomyelinating leukodystrophy-21 (HLD21; OMIM:619310) was first described in 2018 (PMID: 30584594). Reported phenotypes include developmental delay, loss of motor skills, nystagmus, ataxia, dystonia and spasticity, growth delay, microcephaly, gastrointestinal issues, cryptorchidism, hypogonadotropic hypogonadism, hypodontia, and hypomyelination.
Three variants in three unrelated patients have been described in the literature. Dorboz et al described two unrelated patients, both from consanguineous parents and both from Algeria, who each harbor the same homozygous mutation (c.212T>C; p.Arg41Trp). A third individual was described in Perrier, et al, 2024, with compound heterozygous variants (c.322G>T; p.Asp108Tyr and c.200_327del; p.Glu67Glyfs*18). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern in these cases, and found that the spectrum of phenotypic variability could exist. Therefore, these cases have been lumped into one entity, HDL21 (OMIM:619310).
The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is supported by experimental evidence, namely evidence related to biochemical function. There are several studies that demonstrate the the function of the POL3 complex (PMID: 33558764, PMID:34395538, PMID:16362040), of which POLR3A, POLR3B and POLR1C, and POLR3K (among others) are a part, but few studies describe the specific function of the POLR3K gene. One study by Girbig et al, 2021 (PMID: 33558764) showed that POLR3K is located at the active site of the POL3 complex that transcribes mRNA to produce proteins for myelination. POLR3K forms the portion of the active site that holds the mRNA in a clamp like manner, and variants in POLR3K prevent it from undergoing a conformational switch that enables the release of transcribed mRNA, preventing re-use and thus decreasing efficiency of transcription.
In summary, there is limited evidence supporting the relationship between POLR3K and HDL21, also referred to as POLR3K-related disorder. More experimental and case level evidence is needed to establish a definitive disease association. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date September 10, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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