Recessive Mutations in NDUFA2 Cause Mitochondrial Leukoencephalopathy

Perrier Stefanie (Orcid ID: 0000-0002-6881-7573) Recessive Mutations in NDUFA2 Cause Mitochondrial Leukoencephalopathy (Short Report) Stefanie Perrier1†, Laurence Gauquelin1,2†, Martine Tétreault3,4, Luan Tran1,2,5,6, Neil Webb3,7,8, Myriam Srour1,2,6, John J. Mitchell2,5, Catherine Brunel-Guitton7, Jacek Majewski3,4, Valynne Long9, Stephanie Keller10, Michael J. Gambello9, Cas Simons11, Care4Rare Canada Consortium, Adeline Vanderver12,13, and Geneviève Bernard1,2,5,6* 1 Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. 2 Department of Pediatrics, McGill University, Montreal, QC, Canada. 3 Department of Human Genetics, McGill University, Montreal, QC, Canada. 4 McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada. 5 Department of Medical Genetics, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada. 6 Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada. 7 Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, QC, Canada. 8 Montreal Neurological Institute, McGill University, Montreal, QC, Canada. 9 Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, GA, USA. 10 Department of Pediatrics, Division of Pediatric Neurology, Emory University School of Medicine, Atlanta, GA, USA. 11 Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia. 12 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 13 Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA. † Both authors contributed equally. *Correspondence to: Dr. Geneviève Bernard Research Institute of the McGill University Health Centre 1001 boul Décarie EM02224 (CHHD Mail Drop Point #EM03211 (Cubicle C)) Montréal, QC H4A3J1, Canada. This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cge.13126 This article is protected by copyright. All rights reserved. Email: [email protected] Telephone: 514-934-1934 ext.23380 Fax: 514-933-4149 Conflict of Interest: The authors declare no conflicts of interest. Acknowledgements The authors are grateful to the patients and their families for their participation. This work was performed under the Care4Rare Canada Consortium, funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Génome Québec, Children’s Hospital of Eastern Ontario Foundation and Fondation Leuco Dystrophies. This study was supported by grants from MitoCanada, Fondation les Amis d’Eliott and Réseau de Médecine Génétique Appliquée. We wish to acknowledge the McGill University and Génome Québec Innovation Centre for use of their high throughput sequencing platform. GB has received a Research Scholar Junior 1 award from the Fonds de Recherche du Québec en Santé (2012-2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017-2022). SP is supported by the Max Stern Scholarship from McGill University, and the Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research. MT is supported by a post-doctoral fellowship from the Canadian Institutes of Health Research. JJM receives research support from the Harpur Foundation. AV is supported by the Kamens family. This article is protected by copyright. All rights reserved. Abstract Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report two patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole exome sequencing revealed a homozygous mutation in NDUFA2 (c.134A>C, p.Lys45Thr). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c.134A>C, p.Lys45Thr; c.225del, This article is protected by copyright. All rights reserved. p.Asn76Metfs*4). Only one other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2. Keywords Complex I deficiency, Leukodystrophy, Leukoencephalopathy, NDUFA2, Whole exome sequencing Introduction The first enzyme complex of the mitochondrial respiratory chain oxidative phosphorylation system, NADH-ubiquinone oxidoreductase, is most commonly implicated in deficiencies of the respiratory chain (1). Mitochondrial diseases due to complex I deficiency result in a broad range of clinical symptoms, frequently involving the central nervous system (2). Various pathogenic mutations have been identified in genes encoding complex I subunits, which are commonly associated with isolated complex I deficiency (MIM 252010) (3). Human complex I is composed of 44 different subunits, including 14 core subunits responsible for energy transduction through the transfer of electrons and translocation of protons (4). The remaining 30 accessory subunits have several other suspected functions such as assisting in enzyme assembly, This article is protected by copyright. All rights reserved. providing structural support, shielding core subunits from oxidative damage, and modulating enzyme activity (2,5). NADH-ubiquinone oxidoreductase subunit A2 (NDUFA2) is an accessory subunit located in the distal matrix arm of complex I, and structural analysis has revealed similarities to thioredoxin-related proteins (6). The exact role of NDUFA2 has yet to be defined, but proposed functions include complex I iron-sulfur cluster assembly and upkeep, and use of redox processes for assembly or regulation of enzymatic activity (6,7). Only one patient has been previously described with a homozygous splice site mutation in NDUFA2 (c.208+5G>A) (MIM 602137) causing abnormal splicing of exon 2. This patient exhibited a clinical presentation of Leigh syndrome (MIM, 256000) (8). Here, we present for the first time two patients with cystic leukoencephalopathy associated with novel pathogenic variants in NDUFA2 identified by whole exome sequencing (WES). Materials and Methods Patient Recruitment and Ethics Approval Using MRI pattern recognition, a first patient with unsolved cystic leukoencephalopathy suggestive of complex I deficiency was identified. Biochemical analysis confirmed complex I deficiency, and a homozygous NDUFA2 mutation was identified through WES. Review of a large biorepository of patients with genetically This article is protected by copyright. All rights reserved. undetermined leukoencephalopathies who underwent whole exome or genome sequencing allowed us to identify a second patient with a compatible clinical and radiological phenotype and recessive mutations in NDUFA2. Written informed consent from all subjects or their legal representatives was obtained. This study was approved by the ethics committees of the Montreal Children’s Hospital and the Children’s Hospital of Philadelphia. Biochemical and Genetic Analysis Detailed methods for the biochemical and genetic analyses are provided in the Supporting Information (Appendix S1, Tables S1-S2). The novel disease-causing variants have been listed in the Single Nucleotide Polymorphism Database (dbSNP; https://www.ncbi.nlm.nih.gov/projects/SNP/; rs757982865 and rs863224084), and phenotypic information has been submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/; SCV000584198 and SCV000584199) and PhenomeCentral (https://phenomecentral.org). Results Patient 1, a girl, was born at term after an uneventful pregnancy. Her parents, first cousins from Pakistan, had a first child that died at age 3 years following a febrile illness and seizures, as well as three other clinically unaffected children (Fig. S1). This article is protected by copyright. All rights reserved. Patient 1 presented at 8 months with encephalopathy, hepatomegaly and hyperammonemia. A diagnosis of primary systemic carnitine deficiency was made based on very low plasma carnitine levels (free carnitine 1 nmol/ml, normal 38±21). This condition is associated with a broad clinical spectrum, including an infantile metabolic presentation characterized by episodes of decompensation with poor feeding and lethargy, typically triggered by a febrile illness or fasting. Hepatomegaly, hypoketotic hypoglycemia, and hyperammonemia can be seen with the episodes of decompensation (9). Despite appropriate treatment, patient 1 exhibited developmental regression until age 12 months, after which she stabilized. Her examination was significant for severe spasticity and other upper motor neuron signs, predominantly

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