title: Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants inNDUFB11.
abstract: Variants inNDUFB11,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 inNDUFB11(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 inHCCS(which encodes an important mitochondrially targeted protein) andCOX7B,which, likeNDUFB11,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 thatNDUFB11variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related).
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.|Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, BT9 7AB, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Rea
authors.affiliation: Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, United Kingdom.
authors.forename: Tessa
authors.initials: T
authors.lastname: Homfray
authors.affiliation: Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, United Kingdom.
authors.forename: Jan
authors.initials: J
authors.lastname: Till
authors.affiliation: Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, United Kingdom.
authors.forename: Ferran
authors.initials: F
authors.lastname: Roses-Noguer
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Buchan
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Wilkinson
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.
authors.forename: Alicja
authors.initials: A
authors.lastname: Wilk
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.
authors.forename: Roddy
authors.initials: R
authors.lastname: Walsh
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.
authors.forename: Shibu
authors.initials: S
authors.lastname: John
authors.affiliation: Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, BT9 7AB, United Kingdom.
authors.forename: Shane
authors.initials: S
authors.lastname: McKee
authors.affiliation: Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, BT9 7AB, United Kingdom.
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Stewart
authors.affiliation: Department of Clinical Genetics, Laboratory Medicine, The Queen Elizabeth University Hospital, Glasgow G51 4TF, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Murday
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Histopathology Department, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Ashworth
authors.affiliation: Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, United Kingdom.
authors.forename: A John
authors.initials: AJ
authors.lastname: Baksi
authors.affiliation: National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.|Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, United Kingdom.
authors.forename: Piers
authors.initials: P
authors.lastname: Daubeney
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.|Royal Brompton and Harefield NHS Foundation Trust, London SW3 6NP, United Kingdom.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Prasad
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.
authors.forename: Paul J R
authors.initials: PJR
authors.lastname: Barton
authors.affiliation: National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.|MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom.|National Heart Centre Singapore, Singapore 169609, Singapore.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.affiliation: NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London SW3 6NP, United Kingdom.|National Heart and Lung Institute, Imperial College London, London SW3 6NP, United Kingdom.|MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: James S
authors.initials: JS
authors.lastname: Ware
keywords: Wolff–Parkinson–White syndrome; asymmetric, linear skin defects; dilated cardiomyopathy; left ventricular noncompaction cardiomyopathy; linear hyperpigmentation; microphthalmos; oncocytic cardiomyopathy; ventricular fibrillation