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Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11

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Title: Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11
Authors: Rea, G
Homfray, T
Till, J
Roses-Noguer, F
Buchan, RJ
Wilkinson, S
Wilk, A
Walsh, R
John, S
McKee, S
Stewart, FJ
Murday, V
Taylor, RW
Ashworth, M
Baksi, AJ
Daubeney, P
Prasad, S
Barton, PJR
Cook, SA
Ware, JS
Item Type: Journal Article
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).
Issue Date: 4-Nov-2016
Date of Acceptance: 20-Oct-2016
URI: http://hdl.handle.net/10044/1/43473
DOI: http://dx.doi.org/10.1101/mcs.a001271
ISSN: 2373-2873
Publisher: Cold Spring Harbor Laboratory Press
Journal / Book Title: Cold Spring Harbor Molecular Case Studies
Volume: 3
Copyright Statement: © 2017 The Authors. This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse and redistribution provided that the original author and source are credited.
Sponsor/Funder: The Academy of Medical Sciences
Wellcome Trust
Department of Health
Wellcome Trust
Funder's Grant Number: WHCC_P48756
HICF-R6-373
HICF-R6-373
107469/Z/15/Z
Open Access location: http://molecularcasestudies.cshlp.org/content/3/1/a001271
Article Number: a001271
Appears in Collections:Institute of Clinical Sciences