The association of POLR3A variants with autosomal recessive tremor-ataxia with central hypomyelination (TACH), leukodystrophy with oligodontia (LO), and hypomyelination, hypodontia and hypogonadotropic hypogonadism (4H) syndrome was first described in 2011 (Bernard, et al. 2011, PMID: 21855841). Variants were then described in association with Wiedemann-Rautenstrauch syndrome (WRS) (PMID: 30414627) in 2018. Per criteria outlined by the Clingen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern; and found that the spectrum of phenotypic variability could exist between the described disease entities. Therefore, the prior disease entities have been lumped into one entity, POLR3A-Related Disorders (MONDO:0700276). Clinical characteristics include a variable age of onset with a spectrum of global developmental delay, failure to thrive, hypomyelinating leukodystrophy, neurological dysfunction, dental abnormalities, and hypogonadotropic hypogonadism. POLR3A is the largest subunit of RNA Polymerase III, which transcribes ribosomal, transfer, and nuclear RNAs (PMID: 34395528). Included in this curation are twelve unique variants found in nine subjects across four publications. Four of the twelve variants are predicted or proven null variants (canonical splice site variants or nonsense), the remainder are missense variants. Four of the variants had functional data supporting pathogenicity of the variant (PMID: 21855841, PMID: 30898877, PMID:38561452). Two variants had points upgraded due to variant recurrence across non-related affected patients. The mechanism of function is loss-of-function. Gene-disease relationship is supported by mouse models with POLR3A mutations (PMID: 38168294, PMID: 34583988). The gene-disease pair has had replication over time showing convincing evidence. More evidence in the literature is present, but the maximum score required for genetic evidence has been reached (12 points). To summarize, there is definitive evidence supporting the relationship between POLR3A and POLR3A-Related Disorders, with rigorous and reproducible evidence in clinical and research settings. This gene-disease curation based on ClinGen criteria was approved by the Leukodystrophy and Leukoencephalopathy GCEP on 8/28/2024 (SOP version 10).
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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.