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

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).

Keywords: Wolff–Parkinson–White syndrome; asymmetric, linear skin defects; dilated cardiomyopathy; left ventricular noncompaction cardiomyopathy; linear hyperpigmentation; microphthalmos; oncocytic cardiomyopathy; ventricular fibrillation.

Figure 1.

(A) Sequence electropherogram from genomic DNA of child affected by histiocytoid cardiomyopathy (CM) from the family trio showing the NDUFB11 variant identified by whole-exome sequencing (WES) and confirmed by Sanger sequencing. The image shows part of NDUFB11 exon 2. Forward and reverse reads are shown. The red arrows point to the double peak in the electropherogram showing heterozygosity for the nonsense variant in NDUFB11 c.262C > T. The next-generation sequencing (NGS) coverage at this base was 62×, with 27 reference reads and 33 alternate reads. (B) Sequence electropherogram from genomic DNA of the unaffected mother from the trio showing no evidence of the NDUFB11 sequence-level variant that had been identified in the affected child. The image shows part of NDUFB11 exon 2. Forward and reverse reads are shown. The red arrows point to the base where the nonsense variant in NDUFB11 c.262C > T was detected in the affected daughter. The coverage at this base on WES was 50×, with no evidence of the variant. (C) Sequence electropherogram from genomic DNA of the unaffected father from the trio showing no evidence of the NDUFB11 variant that was identified in the affected child. The image shows part of NDUFB11 exon 2. Forward and reverse reads shown. The red arrows point to the base where the nonsense variant in NDUFB11 c.262C > T was detected in the affected daughter. The coverage at this base on WES was 26×, with no evidence of the variant.

Figure 2.

Histology of histiocytoid cardiomyopathy. Longitudinal section of myocardium from an infant with histiocytoid cardiomyopathy. A few normal myocytes are present in the lower part of the field. The remaining cells are histiocytoid myocytes.