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Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull\u2019s eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibroblasts from two patients further confirmed the functional defect demonstrating reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol, the substrate of CRLS1. Proteomic profiling of patient cells and mouse Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. These findings support that deleterious variants in CRLS1 cause an autosomal recessive mitochondrial disease, presenting as a severe encephalopathy with multi-systemic involvement. Furthermore, we identify key signatures in cardiolipin and proteome profiles across various degrees of cardiolipin loss, facilitating the use of omics technologies to guide future diagnosis of mitochondrial diseases.<\/jats:p>","DOI":"10.1093\/hmg\/ddac040","type":"journal-article","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T12:06:36Z","timestamp":1644235596000},"page":"3597-3612","source":"Crossref","is-referenced-by-count":41,"title":["Deleterious variants in<i>CRLS1<\/i>lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease"],"prefix":"10.1093","volume":"31","author":[{"given":"Richard G","family":"Lee","sequence":"first","affiliation":[{"name":"Telethon Kids Institute , Northern Entrance, Perth Children's Hospital, Nedlands, WA 6009 , Australia"},{"name":"Harry Perkins Institute of Medical Research , QEII Medical Centre, Nedlands, WA 6009 , Australia"},{"name":"ARC Centre of Excellence in Synthetic Biology , Centre for Medical Research, The University of Western Australia, QEII Medical Centre, Nedlands, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanti","family":"Balasubramaniam","sequence":"additional","affiliation":[{"name":"Genetic Metabolic Disorders Service , The Children\u2019s Hospital at Westmead, Sydney, NSW 2145 , Australia"},{"name":"Discipline of Genomic Medicine , Sydney Medical School, University of Sydney, Sydney, NSW 2006 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Stentenbach","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute , Northern Entrance, Perth Children's Hospital, Nedlands, WA 6009 , Australia"},{"name":"Harry Perkins Institute of Medical Research , QEII Medical Centre, Nedlands, WA 6009 , Australia"},{"name":"ARC Centre of Excellence in Synthetic Biology , Centre for Medical Research, The University of Western Australia, QEII Medical Centre, Nedlands, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Kralj","sequence":"additional","affiliation":[{"name":"School of Chemistry , The University of Melbourne, Parkville, VIC 3010 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"McCubbin","sequence":"additional","affiliation":[{"name":"Australian Institute for Bioengineering and Nanotechnology , and Queensland Node of Metabolomics Australia,The University of Queensland, St Lucia, QLD 4072 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Padman","sequence":"additional","affiliation":[{"name":"Centre for Microscopy , Characterisation and Analysis, The University of WA, Perth, WA 6009 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Smith","sequence":"additional","affiliation":[{"name":"Discipline of Genomic Medicine , Sydney Medical School, University of Sydney, 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