Biallelic POLR3B variants were first reported in association to neurologic disease in 2011 (Saitsu et al., PMID: 22036171). Reported phenotypes include 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 (Bernard et al., PMID: 22855961). Prior to this report, the first report of cerebellar hypoplasia with endosteal sclerosis was described in 1986 (Stoll et al. PMID: 3729252). Heterozygous POLR3B variants were first reported in association with neurologic disease in 2021. Reported phenotypes include ataxia, spasticity, and demyelinating neuropathy (Djordjevic et al., PMID: 33417887). 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 (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). 16 variants (missense, splice site, nonsense, frameshift) that have been reported in 9 probands in 7 publications (PMIDs: 22036171, 22036172, 35434302,36650939, 27512013, 30548255, 31577365) are included in this curation. More evidence is available in the literature, and a maximum score of 12 for genetic evidence has been reached (max 12). The mechanism of pathogenicity is reported to be loss of function (Saitsu et al., PMID: 22036171). This gene-disease relationship is also supported by both zebrafish and mouse models (PMIDs: 37635302, 36650939). In summary, there is definitive evidence supporting the relationship between POLR3B and autosomal recessive 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 February 24, 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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