Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders.
Overview
and 7 other authors
Stephan Zuchner19, Matthis Synofzik12,13, Jan H Veldink20, Jean-Francois Trempe6,7, Alexandra Durr8, Guy A Rouleau1,2,14, Ziv Gan-Or1,2,1420 affiliations
- Department of Human Genetics, McGill University, Montréal, Québec Canada
- The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montréal, Québec Canada
- Broad Institute of Harvard and MIT, Cambridge, MA USA
- Department of Psychiatry, University of Ottawa, Ottawa, ON Canada
- Alberta Children’s Hospital, Medical Genetics, Calgary, Canada
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec Canada
- Centre de Recherche en Biologie Structurale (CRBS), McGill University, Montréal, Québec Canada
- Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, AP-HP, and Reference Center for Rare Diseases «Neurogenetics», Department of Medical Genetic, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Department of Neurology, University Hospital Bonn, Bonn, Germany
- Division of Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
- Department of Neurology and Neurosurgery, McGill University, Montréal, Québec Canada
- Departments of Medicine (Neurology) and Medical Genetics, University of Alberta, Edmonton, Canada
- Reference Center for Rare Diseases «Neurogenetics», Department of Medical Genetic, UMR 5287, Bordeaux University Hospital, and Univ. Bordeaux, CNRS, INCIA, NRGenTeam, Bordeaux, France
- Department of Neurology, Neuromuscular Reference Center, University Hospitals Leuven, Louvain, Belgium
- Department of Clinical Neuroscience, King’s College London, London, UK
- Dr. John T. Macdonald Foundation, Department of Human Genetics and John P, Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL USA
- Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands
Abstract
Background: Biallelic SPG7 mutations cause one of the most common forms of hereditary spastic paraplegia (HSP). Several reports have suggested that heterozygous SPG7 variants may also play a role in HSP, but also in amyotrophic lateral sclerosis (ALS). However, it remains controversial whether heterozygous SPG7 mutations are pathogenic on their own, or if other mechanisms are at play. We recently provided evidence for non-Mendelian inheritance in spastic paraplegia 7 (SPG7), as heterozygous carriers of SPG7 mutations often also carried mutations in other disease-related genes, including AFG3L2, more frequently than expected by chance. Given that SPG7 and AFG3L2 encode interacting subunits of the mitochondrial m-AAA protease complex, we hypothesized that combined heterozygous mutations in these genes may act synergistically to disrupt mitochondrial function and contribute to disease. In this study, we aimed to examine whether digenic heterozygous mutations in SPG7 and AFG3L2 can lead to a spectrum of neurodegenerative disorders.
Methods: We first analyzed genome and exome sequencing data of 6644 unrelated individuals including 4817 motor neuron disorder (MND) and ataxia patients and 1827 controls. We next analyzed an additional 18,748 exome data from rare disease cohorts to further examine the occurrence of variants in SPG7 and AFG3L2.
Results: Among the first 4817 MND and ataxia patients, we identified a total of 6 patients, 4 of whom were unrelated, who carried potentially pathogenic variants in both SPG7 and AFG3L2, in contrast to none in 1827 unrelated controls. Further analysis of the 18,748 additional patients with rare disease, as well as a comprehensive literature review, identified 6 more patients, 5 of whom were unrelated, who had digenic mutations in SPG7 and AFG3L2. In the two families we identified, digenic mutations in SPG7 and AFG3L2 perfectly segregated with the disease. The 12 patients reported here exhibited predominant signs of motor neuron and cerebellar involvement.
Conclusions: Our findings demonstrate that digenic inheritance of concurrent heterozygous mutations in SPG7 and AFG3L2 may cause motor neuron and cerebellar disorders. Screening of the entire SPG7 and AFG3L2 genes in genetically undiagnosed cases of MND and spastic ataxia may help to increase the diagnostic yield.
Supplementary Information: The online version contains supplementary material available at 10.1186/
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- figshare:32142975, at figshare; found in DataCite
- figshare:32142978, at figshare; found in DataCite
Data availability
All data used in this study are described in the Methods section. Data generated as part of this study are available from the corresponding author upon reasonable request.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 27 authors, 6 keywords, 11 MeSH terms, 41 references.
Cite
This paper
Estiar, M. A., Yu, E., Varghaei, P., Ross, J. P., Ashtiani, S., Bayne, A. N., Coarelli, G., Timmann, D., Klockgether, T., Beijer, D., Mengel, D., Coutelier, M., Project MinE ALS Sequencing Consortium, Dion, P. A., Suchowersky, O., Ewenczyk, C., Goizet, C., Stevanin, G., Van Damme, P., . . . Gan-Or, Z. (2026). Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders. BMC medicine, 24(1), 283. https://
BibTeX
@article{estiar2026digen
author = {Estiar, Mehrdad A and Yu, Eric and Varghaei, Parizad and Ross, Jay P and Ashtiani, Setareh and Bayne, Andrew N and Coarelli, Giulia and Timmann, Dagmar and Klockgether, Thomas and Beijer, Danique and Mengel, David and Coutelier, Marie and {Project MinE ALS Sequencing Consortium} and Dion, Patrick A and Suchowersky, Oksana and Ewenczyk, Claire and Goizet, Cyril and Stevanin, Giovanni and Van Damme, Philip and Al-Chalabi, Ammar and Zuchner, Stephan and Synofzik, Matthis and Veldink, Jan H and Trempe, Jean-Francois and Durr, Alexandra and Rouleau, Guy A and Gan-Or, Ziv},
title = {{Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders}},
journal = {BMC medicine},
year = {2026},
month = mar,
volume = {24},
number = {1},
pages = {283},
publisher = {BMC},
issn = {1741-7015},
doi = {10.1186/
url = {https://
pmid = {41877227},
pmcid = {PMC13134353}
}
RIS
TY - JOUR
AU - Estiar, Mehrdad A
AU - Yu, Eric
AU - Varghaei, Parizad
AU - Ross, Jay P
AU - Ashtiani, Setareh
AU - Bayne, Andrew N
AU - Coarelli, Giulia
AU - Timmann, Dagmar
AU - Klockgether, Thomas
AU - Beijer, Danique
AU - Mengel, David
AU - Coutelier, Marie
AU - Project MinE ALS Sequencing Consortium
AU - Dion, Patrick A
AU - Suchowersky, Oksana
AU - Ewenczyk, Claire
AU - Goizet, Cyril
AU - Stevanin, Giovanni
AU - Van Damme, Philip
AU - Al-Chalabi, Ammar
AU - Zuchner, Stephan
AU - Synofzik, Matthis
AU - Veldink, Jan H
AU - Trempe, Jean-Francois
AU - Durr, Alexandra
AU - Rouleau, Guy A
AU - Gan-Or, Ziv
TI - Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders
T2 - BMC medicine
J2 - BMC Med
PY - 2026
DA - 2026/
VL - 24
IS - 1
SP - 283
SN - 1741-7015
PB - BMC
DO - 10.1186/
UR - https://
LA - en
ER -
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