Expanding the Genetic and Phenotypic Spectrum of POLRMT-Related Mitochondrial Disease

Mahmoud R Fassad; Sebastian Valenzuela; Monika Oláhová; Jack J Collier; Charlotte V Y Knowles; Eleni Mavraki; Miriam Elbracht; Nergis Güzel; Thomas Herberhold; Ingo Kurth; Andrea Maier; Larissa Mattern; Carol Saunders; Helen McCullagh; Katrin Õunap; Saskia B Wortmann; Andre Reis; Lei Zhang; Claes M Gustafsson; Robert McFarland; Robert W Taylor

doi:10.1111/cge.70011

Expanding the Genetic and Phenotypic Spectrum of POLRMT-Related Mitochondrial Disease

Clin Genet. 2025 Jun 29. doi: 10.1111/cge.70011. Online ahead of print.

Authors

Mahmoud R Fassad^{1

2}, Sebastian Valenzuela³, Monika Oláhová^{1

4}, Jack J Collier^{1

5}, Charlotte V Y Knowles⁶, Eleni Mavraki⁶, Miriam Elbracht⁷, Nergis Güzel⁷, Thomas Herberhold⁸, Ingo Kurth⁷, Andrea Maier⁹, Larissa Mattern⁷, Carol Saunders^{10

11

12}, Helen McCullagh¹³, Katrin Õunap¹⁴, Saskia B Wortmann¹⁵, Andre Reis¹⁶, Lei Zhang^{10

11

12}, Claes M Gustafsson^{3

17}, Robert McFarland^{1

6}, Robert W Taylor^{1

6}

Affiliations

¹ Mitochondrial Research Group, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
² Human Genetics Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
³ Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
⁴ Department of Applied Sciences, Faculty of Health & Life Sciences, Northumbria University, Newcastle upon Tyne, UK.
⁵ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
⁶ NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁷ Center for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany.
⁸ Centre of Epilepsy for Children and Adolescents, Hospital for Neuropediatrics and Neurological Rehabilitation, Schoen Klinik Vogtareuth, Vogtareuth, Germany.
⁹ Medical Treatment Center for Adults With Intellectual Disabilities and/or Severe Multiple Disabilities (MZEB), RWTH Aachen University Hospital, Aachen, Germany.
¹⁰ Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, Missouri, USA.
¹¹ Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, Missouri, USA.
¹² School of Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA.
¹³ Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
¹⁴ Department of Clinical Genetics, Genetic and Personalized Medicine Clinic, Institute of Clinical Medicine, Tartu University Hospital, University of Tartu, Tartu, Estonia.
¹⁵ University Children's Hospital, Paracelsus Medical University (PMU), Salzburg, Austria.
¹⁶ Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
¹⁷ Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.

PMID: 40583167
DOI: 10.1111/cge.70011

Abstract

Mitochondrial diseases are a complex group of conditions exhibiting significant phenotypic and genetic heterogeneity. Genomic testing is increasingly used as the first step in the diagnostic pathway for mitochondrial diseases. We used next-generation sequencing followed by bioinformatic data analysis to identify potentially damaging variants in the POLRMT gene (NM_005035.4) in six new affected individuals. Structural protein analysis predicted the detrimental impact of variants on POLRMT protein structure. Patients show extended phenotypic abnormalities often presenting early in life with features including global developmental delay, cognitive impairment, short stature and muscular hypotonia. This study expands the genetic and phenotypic landscape of mitochondrial disease associated with POLRMT variants.

Keywords: POLRMT; mitochondrial disease; neurodevelopmental disorders; variant classification.

Abstract

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