Journal article

A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein-truncating variant

Nicole J Lake, Luke E Formosa, David A Stroud, Michael T Ryan, Sarah E Calvo, Vamsi K Mootha, Bharti Morar, Peter G Procopis, John Christodoulou, Alison G Compton, David R Thorburn

Human Mutation | WILEY | Published : 2019


Leigh syndrome is a mitochondrial disease caused by pathogenic variants in over 85 genes. Whole exome sequencing of a patient with Leigh-like syndrome identified homozygous protein-truncating variants in two genes associated with Leigh syndrome; a reported pathogenic variant in PDHX (NP_003468.2:p.(Arg446*)), and an uncharacterized variant in complex I (CI) assembly factor TIMMDC1 (NP_057673.2:p.(Arg225*)). The TIMMDC1 variant was predicted to truncate 61 amino acids at the C-terminus and functional studies demonstrated a hypomorphic impact of the variant on CI assembly. However, the mutant protein could still rescue CI assembly in TIMMDC1 knockout cells and the patient's clinical phenotype ..

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Awarded by National Institutes of Health

Awarded by Australian Research Council

Awarded by National Health and Medical Research Council

Funding Acknowledgements

National Institutes of Health, Grant/Award Numbers: R01GM077465, 1R35GM122455; Australian Research Council, Grant/Award Number: DP170103000; National Health and Medical Research Council, Grant/Award Numbers: 1058442, 1078273, 1022896, 1125390, 1068056, 1068409