Michell-Robinson Mackenzie A, Perrier Stefanie, Gauthier Samuel, Derksen Alexa, Sabbagh Quentin, Girbig Mathias, Misiaszek Agata D, Pizzino Amy M, Renaud Deborah L, De Assis Pereira Danilo, Okuda Paola, Karoleska Luciana Maestri, Keller Stephanie, Chong Karen, Gauquelin Laurence, Brais Bernard, Leube Barbara, Grider Tiffany, Shy Michael E, Schüle Rebecca, Minnerop Martina, Bertini Enrico, Nicita Francesco, Tonduti Davide, Müller Christoph W, Vanderver Adeline, Wolf Nicole I, Bernard Geneviève
Department of Neurology and Neurosurgery, McGill University, Montréal, QC H4A 3J1, Canada; Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada.
Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Human Genetics, McGill University, Montréal, QC H4A 3J1, Canada.
HGG Adv. 2025 Jul 18;6(4):100481. doi: 10.1016/j.xhgg.2025.100481.
RNA polymerase III (RNA Pol III)-related disorders (POLR3-RDs) are a group of clinical entities characterized by causal variants in genes encoding RNA Pol III subunits, including POLR3A, POLR3B, POLR1C, POLR1D, POLR3D, POLR3E, POLR3F, POLR3GL, POLR3H, and POLR3K. These typically cause developmental phenotypes affecting the central nervous system; the eyes; connective tissues including bones, teeth, and endocrine axes; and the reproductive system. Similar phenotypes can be caused by variants in separate subunit genes (multigenic). In contrast, variants in the same gene can cause different phenotypes (pleiotropy), making genotype-phenotype correlation challenging. POLR3-RDs, though individually rare, have never been analyzed collectively. To bridge this gap, we developed an extensive database encompassing all published and unpublished cases of POLR3-RDs and conducted the first comprehensive genotype-phenotype correlation study across their entire spectrum. This work contributed new cases, representing 13% of all documented cases in the literature, along with 31 novel variants, accounting for 8% of all identified variants. This database was constructed by systematically reviewing the literature and integrating data from patients under the care of our international network of collaborators. The dataset includes genotype curation, bioinformatics, prior publications, and individual patient outcome information. By leveraging these comprehensive data, we were able to establish clear genotype-phenotype correlations for some pathogenic variants, which will help provide optimal clinical care and genetic counseling (including insights into disease phenotypes and progression) and offer valuable guidance for future clinical trial design and patient stratification.
RNA聚合酶III（RNA Pol III）相关疾病（POLR3-RDs）是一组临床病症，其特征是编码RNA Pol III亚基的基因存在致病变异，这些亚基包括POLR3A、POLR3B、POLR1C、POLR1D、POLR3D、POLR3E、POLR3F、POLR3GL、POLR3H和POLR3K。这些变异通常会导致影响中枢神经系统、眼睛、包括骨骼、牙齿和内分泌轴在内的结缔组织以及生殖系统的发育表型。单独亚基基因的变异（多基因）也可导致类似的表型。相比之下，同一基因的变异可导致不同的表型（多效性），这使得基因型-表型关联具有挑战性。POLR3-RDs虽然个别病例罕见，但从未进行过综合分析。为了填补这一空白，我们建立了一个广泛的数据库，涵盖了所有已发表和未发表的POLR3-RDs病例，并对其整个谱系进行了首次全面的基因型-表型关联研究。这项工作贡献了新病例，占文献中所有记录病例的13%，以及31个新变异，占所有已识别变异的8%。该数据库是通过系统回顾文献并整合来自我们国际合作网络所诊治患者的数据而构建的。数据集包括基因型整理、生物信息学、先前的出版物以及个体患者的预后信息。通过利用这些全面的数据，我们能够为一些致病变异建立明确的基因型-表型关联，这将有助于提供最佳的临床护理和遗传咨询（包括对疾病表型和进展的深入了解），并为未来的临床试验设计和患者分层提供有价值的指导。
