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

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 McFarlandRobert W. Taylor^*

^*Corresponding author for this work

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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.

Original language	English
Number of pages	9
Journal	Clinical Genetics
Early online date	29 Jun 2025
DOIs	https://doi.org/10.1111/cge.70011
Publication status	E-pub ahead of print - 29 Jun 2025

Keywords

variant classification
mitochondrial disease
neurodevelopmental disorders
POLRMT

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Fassad, M. R., Valenzuela, S., Oláhová, M., Collier, J. J., Knowles, C. V. Y., Mavraki, E., Elbracht, M., Güzel, N., Herberhold, T., Kurth, I., Maier, A., Mattern, L., Saunders, C., McCullagh, H., Õunap, K., Wortmann, S. B., Reis, A., Zhang, L., Gustafsson, C. M., ... Taylor, R. W. (2025). Expanding the Genetic and Phenotypic Spectrum of POLRMT ‐Related Mitochondrial Disease. Clinical Genetics. Advance online publication. https://doi.org/10.1111/cge.70011

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title = "Expanding the Genetic and Phenotypic Spectrum of POLRMT ‐Related Mitochondrial Disease",

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 = "variant classification, mitochondrial disease, neurodevelopmental disorders, POLRMT",

author = "Fassad, \{Mahmoud R.\} and Sebastian Valenzuela and Monika Ol{\'a}hov{\'a} and Collier, \{Jack J.\} and Knowles, \{Charlotte V. Y.\} and Eleni Mavraki and Miriam Elbracht and Nergis G{\"u}zel and Thomas Herberhold and Ingo Kurth and Andrea Maier and Larissa Mattern and Carol Saunders and Helen McCullagh and Katrin {\~O}unap and Wortmann, \{Saskia B.\} and Andre Reis and Lei Zhang and Gustafsson, \{Claes M.\} and Robert McFarland and Taylor, \{Robert W.\}",

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month = jun,

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doi = "10.1111/cge.70011",

language = "English",

journal = "Clinical Genetics",

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Fassad, MR, Valenzuela, S, Oláhová, M, Collier, JJ, Knowles, CVY, Mavraki, E, Elbracht, M, Güzel, N, Herberhold, T, Kurth, I, Maier, A, Mattern, L, Saunders, C, McCullagh, H, Õunap, K, Wortmann, SB, Reis, A, Zhang, L, Gustafsson, CM, McFarland, R & Taylor, RW 2025, 'Expanding the Genetic and Phenotypic Spectrum of POLRMT ‐Related Mitochondrial Disease', Clinical Genetics. https://doi.org/10.1111/cge.70011

TY - JOUR

T1 - Expanding the Genetic and Phenotypic Spectrum of POLRMT ‐Related Mitochondrial Disease

AU - Fassad, Mahmoud R.

AU - Valenzuela, Sebastian

AU - Oláhová, Monika

AU - Collier, Jack J.

AU - Knowles, Charlotte V. Y.

AU - Mavraki, Eleni

AU - Elbracht, Miriam

AU - Güzel, Nergis

AU - Herberhold, Thomas

AU - Kurth, Ingo

AU - Maier, Andrea

AU - Mattern, Larissa

AU - Saunders, Carol

AU - McCullagh, Helen

AU - Õunap, Katrin

AU - Wortmann, Saskia B.

AU - Reis, Andre

AU - Zhang, Lei

AU - Gustafsson, Claes M.

AU - McFarland, Robert

AU - Taylor, Robert W.

PY - 2025/6/29

Y1 - 2025/6/29

N2 - 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.

AB - 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.

KW - variant classification

KW - mitochondrial disease

KW - neurodevelopmental disorders

KW - POLRMT

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U2 - 10.1111/cge.70011

DO - 10.1111/cge.70011

M3 - Article

SN - 0009-9163

JO - Clinical Genetics

JF - Clinical Genetics

ER -

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

Abstract

Keywords

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