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Mutations in the mitochondrial complex I assembly factor NDUFAF1 cause fatal infantile hypertrophic cardiomyopathy
  1. Elisa Fassone1,2,
  2. Jan-Willem Taanman3,
  3. Iain P Hargreaves4,
  4. Neil J Sebire5,
  5. Maureen A Cleary6,
  6. Michael Burch7,
  7. Shamima Rahman1,6,8
  1. 1Mitochondrial Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK
  2. 2Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Cà Granda, Ospedale Maggiore, Milan, Italy
  3. 3Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK
  4. 4Neurometabolic Unit, National Hospital for Neurology, Queen Square, London, UK
  5. 5Histopathology Unit, Great Ormond Street Hospital, London, UK
  6. 6Metabolic Unit, Great Ormond Street Hospital, London, UK
  7. 7Cardiology Unit, Great Ormond Street Hospital, London, UK
  8. 8MRC Centre for Neuromuscular Diseases, National Hospital for Neurology, London, UK
  1. Correspondence to Dr Shamima Rahman, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; s.rahman{at}


Background Hypertrophic cardiomyopathy (HCM) is frequently fatal in infancy. Mitochondrial disease causing infantile HCM is characterised by extreme biochemical and genetic heterogeneity, but deficiency of respiratory chain complex I is observed relatively frequently. Identification of the precise genetic basis has prognostic implications for the likelihood of neurological involvement.

Objective The authors' objective is to report two heterozygous missense mutations in the NDUFAF1 gene as a cause of fatal infantile HCM in a patient with isolated complex I deficiency.

Methods The authors investigated a cohort of 30 paediatric patients with complex I deficiency using biochemical and genetic approaches. The patients were clinically heterogeneous; phenotypes included HCM, Leigh syndrome, other encephalomyopathies and multisystem disease. Complex I assembly was evaluated using Blue Native polyacrylamide gel electrophoresis.

Results Sequence analysis of NDUFAF1 revealed compound heterozygous missense mutations (c.631C>T;p.Arg211Cys and c.733G>A;p.Gly245Arg) in one patient with fatal infantile HCM. These changes were absent in 240 ethnically matched control alleles. No NDUFAF1 mutations were observed in the remaining patients. Functional studies demonstrated a severe reduction in NDUFAF1 protein in Western blots of patient fibroblasts and accumulation of abnormal complex I assembly intermediates on Blue Native polyacrylamide gel electrophoresis.

Conclusions The authors report a case of fatal infantile HCM caused by missense mutations in NDUFAF1 associated with complex I misassembly. Establishing a genetic diagnosis in mitochondrial cardiomyopathy is challenging and achieved in only a minority of cases because of complex genetics. A precise genetic diagnosis is important to provide accurate prognostic and genetic counselling advice regarding recurrence risks and to guide future reproductive options.

  • Mitochondrial respiratory chain
  • hypertrophic cardiomyopathy
  • NADH:ubiquinone oxidoreductase
  • complex I deficiency
  • molecular genetics
  • nutrition and metabolism
  • neuromuscular disease
  • muscle disease
  • molecular genetics

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  • Funding SR is supported by the Great Ormond Street Hospital Children's Charity. This project received grant funding from the Great Ormond Street Hospital/UCL Institute of Child Health Science Development Initiative and was made possible by a British–Italian partnership grant from the British Council.

  • Competing interests None.

  • Ethics approval Ethics approval was provided by the Great Ormond Street Hospital/Institute of Child Health research ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.