Journal article
Comprehensive Genotype-Phenotype Analysis in POLR3-Related Disorders
HGG advances, Vol.6(4), 100481
10/2025
DOI: 10.1016/j.xhgg.2025.100481
PMCID: PMC12391809
PMID: 40684265
Abstract
RNA Polymerase III (POLR3)-related disorders (POLR3-RD) are a group of clinical entities characterized by causal variants in genes encoding 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, 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-RD, 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 To bridge this gap, we developed an extensive database encompassing all published and unpublished cases of POLR3-RD and conducted the first comprehensive genotype-phenotype correlation study across their entire spectrum.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 this comprehensive data, we were able to establish clear genotype-phenotype correlations for some pathogenic variants, which will help provide optimal clinical care, genetic counseling (including insights into disease phenotypes and progression), and offer valuable guidance for future clinical trial design and patient stratification.
Details
- Title: Subtitle
- Comprehensive Genotype-Phenotype Analysis in POLR3-Related Disorders
- Creators
- Mackenzie A Michell-Robinson - McGill University Health CentreStefanie Perrier - McGill University Health CentreSamuel Gauthier - McGill University Health CentreAlexa Derksen - McGill University Health CentreQuentin Sabbagh - McGill University Health CentreMathias Girbig - Max Planck Institute for Terrestrial MicrobiologyAgata D Misiaszek - Friedrich Miescher InstituteAmy M Pizzino - Children's Hospital of PhiladelphiaDeborah L Renaud - Mayo ClinicDanilo De Assis Pereira - Universidade Estadual de Campinas (UNICAMP)Paola Okuda - Psychiatry and Medical Psychology, Federal University of São Paulo (UNIFESP), São Paulo, São Paulo, 5445030, BrazilLuciana Maestri Karoleska - Universidade Federal de São PauloStephanie Keller - Emory UniversityKaren Chong - Mount Sinai HospitalLaurence Gauquelin - Université LavalBernard Brais - McGill UniversityBarbara Leube - Heinrich Heine University DüsseldorfTiffany Grider - University of IowaMichael E Shy - University of IowaRebecca Schüle - Dr. John T. Macdonald FoundationMartina Minnerop - Heinrich Heine University DüsseldorfEnrico Bertini - Mylan (Switzerland)Francesco Nicita - Hospital Center for the Care and Treatment of Leukodystrophies and Associated Conditions (COALA), Milan, Lombardy, 20154, ItalyDavide Tonduti - Bambino Gesù Children's HospitalChristoph W Müller - European Molecular Biology LaboratoryAdeline Vanderver - University of PennsylvaniaNicole I Wolf - Amsterdam NeuroscienceGeneviève Bernard - McGill University Health Centre
- Resource Type
- Journal article
- Publication Details
- HGG advances, Vol.6(4), 100481
- DOI
- 10.1016/j.xhgg.2025.100481
- PMID
- 40684265
- PMCID
- PMC12391809
- NLM abbreviation
- HGG Adv
- ISSN
- 2666-2477
- eISSN
- 2666-2477
- Publisher
- CELL PRESS
- Grant note
- Canadian Institutes of Health Research (CIHR): PJT-168887 Montreal Children's Hospital Foundation/Leuco ActionVanier Canada Graduate ScholarshipMcGill University Faculty of MedicineFonds de Recherche du Quebec-Sante (FRQS) Doctoral ScholarshipFondation du Grand defi Pierre Lavoie Doctoral ScholarshipMcGill Faculty of Medicine F.S.B. Miller FellowshipResearch Institute of the McGill University Health Centre Desjardins Studentship in Child Health ResearchCIHR Master's ScholarshipResearch Institute of the McGill University Health Centre Master's StudentshipFRQSCanadian Gene Cure Advanced Therapies for Rare Disease (Can-GARD)CIHRFaculty of Medicine, Universite LavalChercheur de Merite award from the FRQSEuropean Reference Network for Rare Neurological Diseases: 739510
The group would like to acknowledge the generous support of the patients and families contributing to this research. This study was funded by research grants from the Canadian Institutes of Health Research (CIHR; PJT-168887) and the Montreal Children's Hospital Foundation/Leuco Action. M.A.M.-R. would like to acknowledge the Vanier Canada Graduate Scholarship and the McGill University Faculty of Medicine for their generous support. S.P. has been supported by the Fonds de Recherche du Quebec-Sante (FRQS) Doctoral Scholarship, the Fondation du Grand defi Pierre Lavoie Doctoral Scholarship, the McGill Faculty of Medicine F.S.B. Miller Fellowship, and the Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research. S.G. received support from the CIHR Master's Scholarship and the Research Institute of the McGill University Health Centre Master's Studentship. L.G. has received grants from the Canadian Gene Cure Advanced Therapies for Rare Disease (Can-GARD, 2018) and from R.S. McLaughlin and Teva Canada Innovation funds from the Faculty of Medicine, Universite Laval (2018). F.N. and E.B. are members of the European Reference Network for Rare Neurological Diseases, project ID no. 739510. G.B. has received the Clinical Research Scholar Junior 1 Award from the FRQS (2012-2016), the New Investigator Salary Award from the CIHR (2017-2022), the Clinical Research Scholar Senior award from the FRQS (2022-2025), and the Chercheur de Merite award from the FRQS (2025-2029).
- Language
- English
- Electronic publication date
- 07/18/2025
- Date published
- 10/2025
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984865317302771
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