Multi-omics approach characterises CRLS1 deficiency, a novel mitochondrial disorder

Abstract

Introduction: The increasing integration of high-throughput genomic strategies, particularly whole exome (WES) and genome sequencing (WGS) has revolutionised mitochondrial diagnostics with the discovery of a growing list of novel disease genes. Application of ‘multi-omics’ technologies including proteomics, lipidomics and transcriptomics will improve the diagnostic gap. Case report: We present two individuals with progressive encephalopathy and biallelic variants identified on WES in the cardiolipin synthase 1 (CRLS1) gene. Additionally, the female infant had hypertrophic cardiomyopathy, bull’s eye maculopathy, auditory neuropathy, diabetes insipidus and died at 3.5 months. The 19-year-old male presented with neurodevelopmental regression, congenital nystagmus, sensorineural hearing loss and acquired microcephaly. Results: Respiratory chain enzyme analysis of skeletal muscle showed low Complex IV activity in the first patient. Mitochondrial morphology and biogenesis were impaired in her fibroblasts. Expression of wild-type CRLS1 restored her abnormal fibroblast morphology. Fibroblast proteomic profiling and mouse Crls1 knockout cell lines identified endoplasmic reticular, mitochondrial stress responses, and varying degrees of cardiolipin insufficiency. Lipid profiling in both demonstrated reduced cardiolipin levels, altered acyl-chain composition and significantly increased levels of phosphatidylglycerol. Collectively, these findings support that deleterious CRLS1 variants cause a novel mitochondrial disorder with multisystemic involvement. Conclusion: Innovative multi-omics approaches help establish novel diagnoses and provide insights into disease mechanisms.