Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11
- Gillian Rea1,2,3,
- Tessa Homfray4,
- Jan Till4,
- Ferran Roses-Noguer4,
- Rachel J. Buchan1,2,
- Sam Wilkinson1,2,
- Alicja Wilk1,2,
- Roddy Walsh1,2,
- Shibu John1,2,
- Shane McKee3,
- Fiona J. Stewart3,
- Victoria Murday5,
- Robert W. Taylor6,
- Michael Ashworth7,
- A. John Baksi4,
- Piers Daubeney2,4,
- Sanjay Prasad1,4,
- Paul J.R. Barton1,2,
- Stuart A. Cook2,8,9,10 and
- James S. Ware1,2,8,10
- 1NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom;
- 2National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom;
- 3Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, BT9 7AB, United Kingdom;
- 4Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, United Kingdom;
- 5Department of Clinical Genetics, Laboratory Medicine, The Queen Elizabeth University Hospital, Glasgow G51 4TF, United Kingdom;
- 6Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom;
- 7Histopathology Department, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom;
- 8MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom;
- 9National Heart Centre Singapore, Singapore 169609, Singapore
- Corresponding authors: j.ware{at}imperial.ac.uk, stuart.cook{at}nhcs.com.sg
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↵10 Joint senior authors
Abstract
Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related).
- asymmetric, linear skin defects
- dilated cardiomyopathy
- left ventricular noncompaction cardiomyopathy
- linear hyperpigmentation
- microphthalmos
- oncocytic cardiomyopathy
- ventricular fibrillation
- Wolff–Parkinson–White syndrome
- Received July 6, 2016.
- Accepted October 20, 2016.
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