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).
Highlights
NDUFB11 (OMIM ∗300403) variants have recently been independently proposed to cause histiocytoid cardiomyopathy (Shehata et al 2015) and microphthalmia with linear skin defects syndrome (MLS; OMIM 309801) (van Rahden et al 2015)
We describe a new case of histiocytoid CM in whom we identified a de novo nonsense variant in NDUFB11 (c.262C > T; p.(Arg88∗))
Seventy five percent of cases of histiocytoid CM present in female infants (Shehata et al 2015), often below 2 yr of age (Gilbert-Barness and Barness 2006), and the identification of NDUFB11, found on Xp11.23, as an underlying cause explains the large excess of affected females
Summary
NDUFB11 (OMIM ∗300403) variants have recently been independently proposed to cause histiocytoid cardiomyopathy (histiocytoid CM; OMIM 500000) (Shehata et al 2015) and microphthalmia with linear skin defects syndrome (MLS; OMIM 309801) (van Rahden et al 2015). Histiocytoid CM is a rare, distinctive form of cardiomyopathy with approximately 150 cases reported worldwide, it has numerous synonyms including oncocytic cardiomyopathy (Shehata et al 2011). Associated cardiac abnormalities include ventricular and atrial septal defects, endocardial fibroelastosis, and hypoplastic left heart syndrome (Shehata et al 1998). Variants in mitochondrial DNA (mtDNA) have previously been associated with histiocytoid CM (Vallance et al 2004), but this has not been replicated in further studies. Histological findings in cardiac tissue often show an accumulation of excessive, aberrantly shaped mitochondria, supporting the role of mitochondrial dysfunction in the etiology (Shehata et al 2015)
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