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Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G&lt;T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant.<\/jats:p>","DOI":"10.3390\/cells11193154","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T01:52:21Z","timestamp":1665193941000},"page":"3154","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families"],"prefix":"10.3390","volume":"11","author":[{"given":"Mazhor","family":"Aldosary","sequence":"first","affiliation":[{"name":"Translational Genomics Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maysoon","family":"Alsagob","sequence":"additional","affiliation":[{"name":"Translational Genomics Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"},{"name":"Center of Excellence for Biomedicine, Joint Centers for Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh 11442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan","family":"AlQudairy","sequence":"additional","affiliation":[{"name":"Translational Genomics Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana C.","family":"Gonz\u00e1lez-\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Bioscience Program, Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"},{"name":"Computational Biology Research Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5278-0668","authenticated-orcid":false,"given":"Stefan T.","family":"Arold","sequence":"additional","affiliation":[{"name":"Bioscience Program, Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"},{"name":"Computational Biology Research Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia"},{"name":"Centre de Biologie Structurale (CBS), INSERM, CNRS, Universit\u00e9 de Montpellier, F-34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Anas","family":"Dababo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar A.","family":"Alharbi","sequence":"additional","affiliation":[{"name":"Radiology Department, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawan","family":"Almass","sequence":"additional","affiliation":[{"name":"Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AlBandary","family":"AlBakheet","sequence":"additional","affiliation":[{"name":"Translational Genomics Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia","family":"AlSarar","sequence":"additional","affiliation":[{"name":"Translational Genomics Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"},{"name":"Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alya","family":"Qari","sequence":"additional","affiliation":[{"name":"Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2501-691X","authenticated-orcid":false,"given":"Mysoon M.","family":"Al-Ansari","sequence":"additional","affiliation":[{"name":"Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"},{"name":"Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Ol\u00e1hov\u00e1","sequence":"additional","affiliation":[{"name":"Welcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saif A.","family":"Al-Shahrani","sequence":"additional","affiliation":[{"name":"Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moeenaldeen","family":"AlSayed","sequence":"additional","affiliation":[{"name":"Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"},{"name":"College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6485-8768","authenticated-orcid":false,"given":"Dilek","family":"Colak","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7768-8873","authenticated-orcid":false,"given":"Robert W.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Welcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"NHS Highly Specialized Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"AlOwain","sequence":"additional","affiliation":[{"name":"Department of Medical Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8912-7507","authenticated-orcid":false,"given":"Namik","family":"Kaya","sequence":"additional","affiliation":[{"name":"Translational Genomics Department, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), P.O. Box 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1136\/jmedgenet-2014-102592","article-title":"ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder","volume":"52","author":"Alfadhel","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_2","first-page":"99","article-title":"Hereditary optic neuropathies","volume":"14","author":"Kerrison","year":"2001","journal-title":"Ophthalmol. Clin. N. 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