Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders
Year: 2026
Type: article
Study design: Observational Study
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.
Source: BMC Medicine
Authors: Mehrdad A. Estiar, Eric Yu, Parizad Varghaei, Jay P. Ross, Setareh Ashtiani, Andrew N. Bayne, Giulia Coarelli, Dagmar Timmann, Thomas Klockgether, Danique Beijer, David Mengel, Marie Coutelier, Patrick A. Dion, Oksana Suchowersky, Claire Ewenczyk, Cyril Goizet, Giovanni Stevanin, Philip Van Damme, Ammar Al-Chalabi, Stephan Zuchner, Matthis Synofzik, Jan H. Veldink, Jean-Francois Trempe, Alexandra Durr, Guy A. Rouleau, Ziv Gan-Or
Institutions: Broad Institute, Montreal Neurological Institute and Hospital, McGill University, University of Ottawa, Alberta Children's Hospital, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, Essen University Hospital, University of Duisburg-Essen, University Hospital Bonn, German Center for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, University of Alberta, Université de Bordeaux, Centre Hospitalier Universitaire de Bordeaux, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Universitair Ziekenhuis Leuven, King's College London, University of Miami, Dr. John T. Macdonald Foundation, University Medical Center Utrecht
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
OpenAlex ID: W7140200204