Submission Details

Heterozygous POLR3B variants were first reported in association with neurologic disease in 2021 (Djordjevic et al., PMID: 33417887). Reported phenotypes include ataxia, spasticity, and demyelinating neuropathy (Djordjevic et al., PMID: 33417887). Prior to this report, many patients were clinically diagnosed with Charcot-Marie-Tooth. Biallelic POLR3B variants were first reported in relation to hypomyelinating leukodystrophy, with or without motor dysfunction, progressive cerebellar dysfunction, dystonia, spasticity, cognitive dysfunction, abnormal dentition, short stature (with or without growth hormone deficiency, hypogonadotropic gonadism, and ocular abnormalities (Saitsu et al., PMID: 22036171). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, phenotypic variability, with proposed differences in molecular mechanism. Therefore, the following disease entities have been split into multiple disease entities: autosomal dominant POLR3B-related disorder (including Charcot-Marie-Tooth disease demyelinating, type 1I, OMIM:619742) and autosomal recessive POLR3B-related disorder (Leukodystrophy, hypomyelinating, 8 with or without oligodontia and/or hypogonadotropic hypogonadism OMIM:614381). The latter was previously curated and reached definitive classification The curation for autosomal dominant POLR3B-related disorder includes 21 missense variants that have been reported in 23 probands in 8 publications (PMIDs: 33417887, 34666706, 38002527, 39178560, 35482004, 37897416, 37776383, 39348199) are included in this curation. The maximum score of 12 for genetic evidence was reached. The mechanism of pathogenicity is suggested to be dominant negative due to being “potentially capable of altering the assembly of the functionally active polymerase III pre-initiation complex” (Colona et al., PMID: 38002527, Abasacal-Palacios, et al., PMID: 2934563). De novo POLR3B variants affect the assembly of specific RNA polymerase III subunits (Djordjevic et al., PMID: 33417887). There are no mouse models available for autosomal dominant POLR3B-related disorder. In summary, there is definitive evidence supporting the relationship between POLR3B and autosomal dominant POLR3B-related disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date April 16, 2025 (SOP Version 11).